Orexin Receptors: Pharmacology le Meriana ea Ts'oaetso (2012)

Thomas E. Scammell¹ 'me Christopher J. Winrow²

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Orexin-A le -B (e tsejoang hape ka hore ke hypocretin-1 le -2) ke li-neuropeptides tse hlahisitsoeng ho hypothalamus ea morao-rao e khothalletsang likarolo tse ngata tsa ho tsosa ka li-receptors tsa OX1 le OX2. Ebile, li hlokahala bakeng sa ho phaphama ka tsela e tloaelehileng, kaha tahlehelo ea methapo e hlahisang orexin e baka narcolepsy ho batho le litoeba. Sena se hlahisitse tjantjello e kholo ea ho nts'etsapele lira tse nyane tsa molek'hule orexin receptor antagonists e le mofuta o mocha oa kalafo bakeng sa ho phekola ho hloka boroko. Bohanyetsi ba Orexin, haholoholo bo thibelang OX2 kapa bobeli ba li-OX1 le li-receptors tsa OX2, li khothaletsa ka ho hlaka boroko ba liphoofolo, 'me liphetho tsa kliniki lia khothatsa: Likarolo tse' maloa li litekong tsa Phase III. Joalo ka ha ts'ebetso ea orexin e hlohlelletsa ho hlasimoloha, menyetla ena e mecha e ka ntlafatsa boroko ntle le ho kenya litlamorao tse ngata tse tlisoang ke meriana ea hajoale.

Orexin Peptides

Orexin-A le -B li tsoa ho litlolo tsa pele-pele tsa orexin (1, 2). Orexin-A e na le li-amino acid tsa 33 tse nang le marokho a mabeli a disulfide, mme orexin-B ke li-peptide tse tsamaeang tsa li-amino acid tsa 28 tseo mohlomong e leng li-helpha tse peli tsa alpha (3). Peptide e 'ngoe le e' ngoe e lutse ka har'a terminus ea C, le terminus ea N Oxx-A e boetse e potoloha ka masalla a pyroglutamyl. Li-peptide tsena li kentsoe ka har'a li-vesicles tse teteaneng tsa mantlha 'me hangata li lokolloe ka tatellano (2). Hanyane hanyane hoa tsebahala ka kinetics ea li-orexin, empa orexin-A e bonahala e baka litlamorao tsa boits'oaro bo tšoarellang, mohlomong ka lebaka la liphetoho tsa moraorao tsa phetolelo (1, 4). Li-peptide tsa orexin li bolokiloe hantle lipakeng tsa batho le litoeba, ka tatellano e tšoanang ea orexin-A le li-amino acid tse ling tse peli ho orexin-B (1). Li-vertebrate tse ling tse ngata tse kenyeletsang zebrafish le tsona li hlahisa li-orexin, empa li-invertebrates li bonahala li haelloa ke li-peptide tsa orexin.

Li-peptide tsa orexin li hlahisoa ke sehlopha sa li-neurons se hypothalamus se potileng fornix se fetelang ho hypothalamus ea morao. Boko ba motho bo na le li-neuron tse hlahisang 50,000-80,000 orexin (5, 6), 'me lisele tsena li na le lipakanyo tse pharalletseng libakeng tse ngata tsa boko (7). Tse ling tsa merero e boima ka ho fetesisa ke li-nuclei tse laolang ho hlasimoloha le ho susumetsoa ha maikutlo, ho kenyelletsa le methapo ea kutlo ea methapo ea methapo ea methapo ea methapo ea methapo ea methapo (TMN), li-neurotonergic neurons tsa mokokotlo oa mokokotlong. tikoloho (VTA) (Setšoantšo sa 1). Li-neuron tsa orexin li boetse li tšoara li-neuron tsa cholinergic le tsa noncholinergic bokong ba basal mme li hlahella ka kotloloho ho cortex. Ka likhakanyo tsena, sisteme ea orexin e maemong a loketseng ho hokahanya ts'ebetso ea li-system tse ngata tsa neural tse amehang likarolong tse fapaneng tsa borashe.

 

Setšoantšo sa 1

Sisteme ea orexin e thusa ho kopanya matšoao a susumetsang hore a arabe ka mokhoa o khahlisang. Schematic ena e akaretsa litsela tse behang tseo ka tsona lipontšo li amanang le boroko, khatello ea maikutlo, tlhaselo le tlala li eketsang methapo ea kutlo ea orexin ho tsamaisa likarolo tse fapaneng tsa boroko. ...

Li-neuron tsa orexin le tsona li boemong bo botle ba ho arabela lipontšo tse fapaneng tsa neural (8, 9). Ba amohela lipeeletso tse matla tse tsoang likarolong tsa boksi tse arabelang likarabo tsa khatello le molumo o ikemetseng o kang amygdala le insort cortex, hammoho le li-nuclei tse laolang moputso le khothatso tse kang li-nucleus accumbens le VTA. Tlhahisoleseling e amanang le morethetho oa circadian le nako ea ho tsoha e ka susumetsa methapo ea kutlo ea orexin ka noka ea dorsomedial ea hypothalamus (DMH) (10). Ka ho hokahanya tlhahisoleseling ho tsoa ho tsena tse fapaneng, li-neuron tsa orexin li ka khothaletsa ka mokhoa o nepahetseng maemo a fapaneng. Le ha e so bontšoa, ts'ebetso e sa lokelang ea li-neurone tsa orexin bosiu e kanna ea kenya letsoho boroko hobane batho ba hlobaetsang khafetsa ba bonts'a matšoao a hyperarousal joalo ka tekanyo e matla ea metabolic le molumo oa kutloelo-bohloko (11, 12).

Li-Receptors tsa Orexin

Li-peptides tsa orexin li tlama ka mokhoa o ikhethileng ho li-receptor tsa OX1 le OX2 (OX1R le OX2R, eo hape e tsejoang e le HCRTR1 le HCRTR2) (1). Tsena ke li-receptor tsa G protein- tse kopantsoeng tse nang le libaka tsa 7-transmembrane le tse ling tse tšoanang le li-receptor tse ling tsa neuropeptide. OX1R le OX2R li bolokiloe ka matla ho pholletsa le liphoofolo tse anyesang, ka boitsebiso ba 94% ka tatellano ea amino acid pakeng tsa batho le likhoto (1).

OX1R e tlama orexin-A e nang le tumellano e phahameng (IC₅₀ 20 nM ka tlholisanong e tlamang), empa e na le kamano e tlase haholo bakeng sa orexin-B (IC₅₀ 420 nM) (Setšoantšo sa 2). Khetho ena ea orexin-A e bonahala le ho feta tekanyong ea nakoana ea nakoana ea calcium liseleng tsa CHO tse fetisetsoang le OX1R (EC₅₀ 30 nM ea orexin-A e bapisoang le 2,500 nM bakeng sa orexin-B) (1). OX2R e arolelana 64% amino acid homology le OX1R, empa ha e khethoe hanyane, e tlama orexin-A le -B ka tumellano e phahameng (IC₅₀ 38 nM le 36 nM, ka ho latellana) ((1). Le ha li na le sebopeho se tšoanang le li-receptor tse ling tsa neuropeptide, ha ho na O1R kapa OX2R ha e na kamano e bohlokoa ea li-neuropeptide Y, Secretin, kapa li-peptide tse tšoanang (1, 13).

 

Setšoantšo sa 2

Mechine e tšoaeang ea Orexin. Orexin-A signals ka bobeli ba OX1R le OX2R, athe li-orexin-B li-sign hangata haholo ka OX2R. Li-cascad tse tsoang kahare tse kenngoang liprotheine tsa G li eketsa khalsiamo e kenellang 'me li kenya letsoho sodium / calcium exchanger, e nyenyefatsang ...

OX1R le OX2R mRNA e hlahisoa ka bongata bokong ka mokhoa o ts'oanang le oa li-termeals tsa methapo ea orexin (14). Li-nuclei tse ling tse kang locus coeruleus li bua feela OX1R mRNA, 'me tse ling tse kang TMN li bua feela OX2R mRNA. Likarolo tse ngata tse kang raphe nuclei, VTA, amygdala, le cortex li hlahisa li-receptor ka bobeli, empa hore na OX1R le OX2R li hlahisoa ke li-neuron tse tšoanang li lula li sa tsejoe. Liphuputso tse tšepahalang ka ho fetisisa tsa ho fumana limmapa tsa orexin li hlahlobisitse kabo ea mRNA; lithuto tse sebelisang matla a ho thibela pelehi ho fumana liprotheine tsa orexin receptor li lokela ho shejoa ka hloko hobane li-antisera tse ngata tsa hona joale li ka hlahisa lits'oants'o tse sa hlakang.

Boholo ba lipatlisiso bo shebile bokong, empa li-orexin tse nyane le li-receptor tsa tsona li ka hlahisoa kae kapa kae. Liteko li na le litekanyetso tse lekaneng tsa preR-orexin mRNA, empa polelo ea li-receptor e bonahala e le tlase (1, 15). Orexin le OX2R mRNA li fumanoe ho adrenal cortex (15, 16). Li-neuron tse hlahisang Orexin le tsona li hlalositsoe ho submucosal le myenteric plexuses ea mala le mala a manyane (17), empa tseko ena e ea phehisana hobane e kanna ea emela peptide e kang orexin e aranang le orexin antisera (18). Joalokaha polelo ea orexin peptide kantle ho boko e bonahala e fokola, bahanyetsi ba orexin ha ba na monyetla oa ho hlahisa litlamorao tse kholo.

Mechanisms ea Orexin Receptor

Boithuto bo bongata bo bontšitse hore li-orexins li nyenyefatsa li-neuron le ho eketsa sekhahla sa ho chesa le ho thunya ka metsotso e mengata (19-22). Ka kakaretso, OX1R e nahanoa ho nyalana le G_q, mme OX2R e ka supa ka G_q kapa G_i/G_o, empa mekhoa ea ho kopanya e bonahala e fapana ka mofuta oa sele mme ha e so hlahlojoe ka botlalo li-neuron (16, 23).

Litlamorao tse mpe tsa li-orexins li tsamaisoa ka methapo e mengata ea ionic. Li-neuron tse ling li ka fetoha hantle haholo ka ho thibela lits'ebetso tsa potasiamo, ho kenyelletsoa le lipapatso tsa GIRK (G protein-regated inward rectifier)24). Ntle le moo, ho saena li-receptor tsa orexin ho ka baka keketseho e potlakileng le e tsoelang pele ea khalsiamo e kenang ka har'a liteishene tse nang le motlakase oa matla a motlakase, ka lits'ebetso tse fumanehang tsa nakoana kapa ho tsoa mabenkeleng a marang-rang (1, 25-27). Kamora nako, ts'ebetso ea sodium / calcium exchanger e ka kenya letsoho ho pepeseng li-neurons tse tobileng (28, 29). Ntle le litlamorao tsena tsa postynaptic, li-orexins li ka sebetsa maemong a methapo ea kutlo ho khothaletsa GABA kapa glutamate, ka hona ea hlahisa mathata a mangata ho li-neuron tse tlase.21, 25). Ho supa ha Orexin ho ka hlahisa keketseho ea nako e telele ea thabo ea neuronal: Ka VTA, li-orexin li eketsa palo ea N-methyl-DLi-receptor -aspartate (NMDA) tse kahara membrane ea sele, li etsa hore li-neurons li arabele haholoanyane litlamorao tsa thabo ea glutamate ka lihora tse 'maloa (30, 31). Ka mekhoa ena, ho nahanoa hore orexin e khahlisa li-neuron tse khothalletsang likarolo tse ngata tsa ho hlasimoloha.

Li-neuron tse hlahisang orexin le tsona li hlahisa glutamate, dynorphin, 'me mohlomong li-neuropeptide tse ling tse tsoang ho prepro-dynorphin (32, 33). Ha ho tsejoe letho ka likarolo tsa li-neurotransmitters tsena kapa maemo ao ba lokolloang ka ona, empa e ka ba a bohlokoa 'meleng. Mohlala, li-orexins li khahlisa li-neuron tsa TMN, 'me ho tsamaisana ha dynorphin hape ho fokotsa bokhoni ba thibelo ea "postynaptic", ho ntlafatsa maqhubu a li-neurons tsa TMN (34). Ntle le moo, ha ho bapisoa le litoeba tse haelloang ke li-peptide tsa orexin feela, litoeba tse haelloang ke methapo ea kutlo ea orexin li na le tšekamelo e matla ea ho nona le ho se sebetse ha boroko ba mahlo bo potlakileng (REM).35, 36). Kahoo lihanyetsi tsa orexin li kanna tsa thibela litlamorao tsa li-orexins, empa li-neurotransmitters tsa methapo e kanna ea ba le litla-morao tsa 'mele.

Li-Orexins le Taolo ea Boroko le ho Tsosa

Li-Orexins li hlahisa tse ling tsa litlamorao tsa boitšoaro ba tsona bo matla ho boroko le boroko (Setšoantšo sa 1). Ho enta ha orexin-A kapa -B bokong ba litoeba ho totile ho tsoha ka lihora tse 'maloa, mohlomong ka ho pepesa ka ho toba hoa li-neuron ho locus coeruleus, TMN, raphe nuclei, basal forebrain, le cortex (4, 20, 37-40). Li-neuron tsa orexin li sebetsa hantle 'meleng nakong ea ho tsoha — haholo-holo ho phaphama le ts'ebetso ea makoloi — ebe li lula li khutsitse nakong ea ha motho a sa robala ka REM le REM (41-43). Ka lebaka leo, litla-morao tsa "orexin-A" li maemong a phahameng nakong ea tšebetso, ea ho tsoha ha likhoto, 'me li oela ho halofo ea litekanyo tsa tlhoro ea tsona nakong ea boroko.44). Mokhoa o tšoanang o bonoa ho litšoene tsa squirrel; maemo a holimo haholo a etsahala qetellong ea letsatsi 'me a lula a le holimo haeba monkey e lula e falimehile bosiu (45). Ka hona, li-orexin li kanna tsa khothaletsa boroko nakong ea ts'ebetso e tloaelehileng ho litoeba le litoeba. Mo bathong, pharologano ya diurnal mo maemong a a leng selekanyo sa cerebrospinal fluid (CSF) orexin e lebega e le potlana thata (46, 47), empa mohlomong ke hobane CSF e bokelloa ka kakaretso ho tsoa sebakeng sa lumbar, hole le libaka tsa bohlokoa tsa tokollo.

Tlhokahalo ea li-orexins ka har'a taolo ea ho tsoha ho tloaelehileng ho bonahala ho batho le litoeba tse haelloang ke li-orexin signaling. Batho ba nang le narcolepsy ba na le boroko bo sa feleng, hangata ba ho robala haholo, mme ba nang le "narcolepsy phenotype e felletseng" ba na le tahlehelo e ka bang 90% ea li-neuron tse hlahisang orexin ntle le phokotso e tšoailoeng maemong a CSF a orexin-A (5, 33, 48, 49). Litoeba tsa Orexin peptide knockout le tsona li bonahala li na le boroko bo matla, li sa khone ho boloka nako e telele ea ho falla nakong ea tsona tse mafolofolo (50, 51). Ho khahlisang, litoeba tsena li na le boholo ba ho tsoha bo itekanetseng, empa linako tsa tsona tsa ho phomola li khuts'oane ho feta tse tloaelehileng, 'me li fetoha kapele ho tloha borokoeng (52). Likhoto le lintja tse nang le ts'oaetso ea orexin e sa tsotelleng le tsona li na le mokhoa o ts'oanang, ka linako tse khutšoane tsa ho tsosa li sitisoa ke ho robala hanyane (53, 54). Litlhokomeliso tsena li fana ka bopaki bo matla ba hore li-peptide tsa orexin lia hlokahala molemong oa ho boloka le ho tsitsisa tsoha.

Ntle le boroko ba nako ea motšeare, narcolepsy e hlahisa matšoao ao mohlomong a bonts'ang ho robala ha REM. Ka tloaelo, boroko ba REM bo hlaha feela nakong e tloaelehileng ea boroko, empa bathong le ho liphoofolo tse nang le narcolepsy, boroko ba REM bo ka ba teng ka nako efe kapa efe ea letsatsi (Setšoantšo sa 3) (36, 55, 56). Ntle le moo, batho ba nang le bothata ba ho hlonama ka linako tse ling hangata ba ba le lipono tse hlakileng tsa kelello kapa ho robala litho ka motsotsoana kapa tse peli ha ba robala kapa ha ba tsoha, leha matšoao ana a ka hlaha le ho batho ba tloaelehileng ba seng ba sa robala. Ho makatsang le ho feta ke hore batho ba nang le bothata ba ho hlonama ka linako tse ling ba lula ba e-na le liketsahalo tse khutšoane tsa ho holofala hoo ho bakoang ke maikutlo a matla, a nepahetseng a kang a amanang le ho tšeha kapa ho utloa ho soasoa. Likhechana tse bonolo li ka bonahala e le bofokoli bo poteletseng ba sefahleho kapa molala o nka metsotsoana e seng mekae, empa maemong a matla, motho a ka oela fatše mme a lula a tsitsitse leha a na le bonnete ba metsotso e le 'ngoe kapa tse peli (57). Litali le lintja tse nang le tšoaetso ea tlhaho ea orexin e nang le liphatsa tsa lefutso le tsona li na le liketsahalo tse potlakileng tsa cataplexy bohareng ba ho tsosoa.50, 51, 54). Hoo e ka bang halofo ea batho bohle ba nang le narcolepsy ha ba na liphofu, 'me hangata ba ba le lipono tse matla tse sa bonahaleng le ho holofala boroko. Boholo ba batho bana ba sa ameheng haholo ba na le maemo a tloaelehileng a CSF a orexin, a fana ka maikutlo a hore ba ka ba le likotsi tse fokolang haholo ho li-neuron tse hlahisang orexin (49, 58). Patlisiso e eketsehileng ea kliniki e hlokahala ho bona hore na bahanyetsi ba orexin ba ka baka ho tsitsipana, ho holofala kapa matšoao a mang a lefu la ho robala la REM hobane ho koala ho hlohlona ha orexin signaling ho ka ba le litlamorao tse fapaneng le tse hlahisoang ke tahlehelo e sa feleng ea li-peptide tsa orexin.

 

Setšoantšo sa 3

Karolelano ea mekhatlo ea mahlo e potlakileng (REM) e robala ka taolo le lithuto tsa narcoleptic litulong tsa boroko tse tsoelang pele tsa 24 h. Rekoto e qalile lipakeng tsa 7 le 8 AM, 'me lithuto li ile tsa lumelloa ho robala libapali (n = 10 sehlopheng ka seng). E fetotsoe ho Reference ...

Ho nyane ho tsebahala ka likarolo tse ikhethileng tsa OX1R le OX2R ho laola maikutlo le boroko. Ho tlosoa hoa genetic ho OX1R ho litoeba ha ho na tšusumetso e hlakileng ea ho tsoha le boroko (59), empa tšitiso ea OX2R e hlahisa boroko bo itekanetseng ntle le cataplexy (60). Litoeba tse haelloang ke li-receptor ka bobeli li na boroko bo matla bo tšoanang le bo bonoang litoeba tsa orexin peptide knockout, hape li bonts'a mokhoa o mong o bohloko (61). Ha ho nahanoa hammoho, lipatlisiso tsena li fana ka maikutlo a hore lithethefatsi tse thibelang OX2R li lokela ho sebetsa hantle ka tsela e leka-lekaneng ho khothaletsa boroko, 'me lithethefatsi tse thibelang OX1R le OX2R li lokela ho sebetsa haholo.

Li-Orexins le Taolo ea Takatso ea Monyaka, Meputso, le Lipapali tse ling

Joalokaha lebitso la bona le bolela, li-peptide tsa orexin le tsona ho nahanoa hore li bapala karolo e itseng taolong ea takatso ea takatso ea lijo. Ha e sebelisoa nakong ea leseli, li-orexin li eketsa ho kenella ha lijo ho likhoto, leha karabelo e le nyane haholo ho feta e bonoang ka peptide ea khale ea takatso ea takatso ea lijo e kang neuropeptide Y (1, 62). Leha ho le joalo, ha orexin-A e fanoa nakong ea lefifi ha likhoto li ja ka bongata, ha e eketse lijo tse ngata, ho fana ka maikutlo a hore keketseho ea ho fepa nakong ea khanya e ka hlaha ka keketseho ea mohatsela.63). Ho ntse ho le joalo, li-neuron tsa orexin li arabela ka mokhoa o hlakileng matšoao a takatso ea lijo: Liphuputso tse 'maloa li bontšitse hore matsatsi a 1-2 a ho itima lijo a etsa hore li-neurone tsa orexin li be le menahano e menang habeli ea prero-orexin mRNA (1, 64). Karolo e 'ngoe, matsoao ana a takatso ea lijo a ka arolelanoa le ho kenella ka neural ho tsoa ho arcuate le ventromedial nuclei ea hypothalamus (8, 9). Ntle le moo, li-neuron tsa orexin li arabela ka ho toba matšoao a metabolic: Li khahloa ke ghrelin kapa boemo bo tlase ba tsoekere (e bonts'ang tlala) le ho thibeloa ke leptin (sesupo sa mabenkele a mangata a matla) (65-67). Ha e tingoa lijo bakeng sa ho feta 12 h, litoeba li na le ts'ebetso e kholo le ts'ebetso ea popom, eo e ka bang karabelo ho tlala e qalang. Leha ho le joalo, litoeba tse haelloang ke li-neuron tsa orexin li bonts'a likarabo tse nyane haholo ha lijo li haella, ho fana ka maikutlo a hore matšoao a amanang le tlala a etsa joalo ka li-neuron tsa orexin ho khanna ho tsosa moferefere, ho tsitsa le boits'oaro bo bong bo fapaneng (66).

Ho tsosa ho arabela tlala ho ka ba karolo ea karolo e pharalletseng ea sistimi ea orexin ho arabela ka maikutlo le litšusumetso tse ka bang molemo. Dopaminergic neurons tsa VTA kahare e matla ea li-neuron tsa nucleus li bokellana, mme tsela ena ea mesolimbic e bapala karolo ea mantlha ho lemalla lithethefatsi tse ngata tsa tlhekefetso. Tsela ena e kanna ea kenya letsoho ho hedonic le likarolo tse susumetsang tsa maikutlo a letsatsi le letsatsi a kang lijo le boitšoaro ba thobalano. Li-neuron tsa orexin li hlahisoa ka meputso e kang lijo kapa morphine (64, 68), 'me li-orexins li thabisa ka ho toba li-neurons tsa VTA le li-nucleus bokellwang ka OX1R le OX2R (69, 70). Li-Orexins hape li etsa hore li-neurons tsa VTA li natefeloe haholo ke ho eketsa tlhahiso ea li-receptor tsa NMDA seleng ea sele ka lihora tse ngata (30, 31). Mofuta ona oa tšebeliso ea nako e telele o ka tlatsa maikutlo a locomotor a bonoang ho litoeba tse tšoaroang khafetsa ka koae, kaha likarabo ka bobeli li ka koaloa ke ho nahana ka mohanyetsi oa OX1R (30, 71). Kahoo li-orexin li ka ntlafatsa ts'ebetso litseleng tse ka susumetsang liphoofolo ho batla lithethefatsi, lijo kapa meputso e meng.

Li-neuron tsa orexin li ka boela tsa kenya letsoho karabong ea boitšoaro le ea boits'oaro mefuteng e meng ea khatello (72). Lintho tse u sithabetsang tse kang ho ts'oaroa ke leoto li kenya tšebetsong methapo ea kutlo ea orexin, hangata e ka hlahisoang ke corticotropin-releasing factor (73). Ha a tobane le khatello ea kelello ea "mouse" e kenang ka har'a eona, likhoto tsa orexin peptide knockout li na le keketseho e nyane ea khatello ea mali le pherekano ho feta litoeba tsa mofuta o mong (WT) (74). Ntle le moo, alXXxant ea mohanyetsi oa OX1R / OX2R e fokotsa likarabo tsa boikemelo ho li-stress tse fapaneng, haholoholo tse hlokang boemo bo phahameng ba ho falimeha (75). Leha ho le joalo, ho na le bopaki bo fokolang ba hore bahanyetsi ba orexin ba fokotsa ho tšoenyeha, 'me e ntse e le potso e bulehileng ea hore na li-orexins li laola likarabo ka boits'oaro ka litlamorao tsa litlamorao tsa tsona.

Li-peptide tsa orexin le tsona li susumetsa taolo ea "autonomic" le metabolism. Li-Orexins li thabisa ka ho toba li-neurons tse laolang molumo oa lentsoe76, 77), le li-orexin li eketsa khatello ea mali, sekhahla sa pelo, molumo oa kutloelo-bohloko, le plasma norepinephrine (78). Tlas'a maemo a tloaelehileng, li-orexins li kanna tsa ba le tšusumetso e nyane ho litekanyetso tsa basal autonomic le metabolic hobane li-orexin peptide Knoutout li na le khatello e tlase ea mali, mme litoeba tse haelloang ke li-neurone tsa orexin li na le tšebeliso e tlase ea matla nakong ea nako ea phomolo 'me li fokola ka mokhoa o nyane (35, 79, 80). Ebile, batho ba bangata ba nang le narcolepsy ba na le boima bo bobebe bo bobebe leha ba ja ka tlase ho tse tloaelehileng81, 82). Sena se ka bakoa ke tekanyo e tlase ea metabolic kapa mohlomong ho ikoetlisa honyenyane, hobane litoeba tsa orexin peptide knockout li na le ts'ebetso e fokolang haholo ho feta e tloaelehileng (51, 83).

Ha ho nahanoa hammoho, litla-morao tsena tsa boits'oaro le 'mele li fana ka maikutlo a hore li-neuropeptide tsa orexin li hokahanya likarolo tse ngata tsa ho tsosa. Li-Orexins li khothaletsa le ho tsitsisa ho tsosa, ho thibela le ho laola boroko ba REM, le ho eketsa pherekano le molumo oa kutloelo-bohloko. Ka ho fetisisa, sistimi ea orexin e kenella nakong eohle ea ho tsoha, mme e ka sebetsa haholo ha e tsamaisoa ke matšoao a ka hare a joalo ka khatello ea maikutlo kapa matšoao a kantle a joalo ka tebello ea moputso. Boitlhotlhollo bona hammoho le mefokolo ea mekhoa ea kalafo ea hajoale e fana ka lebaka la mantlha la ho nts'etsapele maikutlo a orexin e le mokhoa o ikhethileng oa ho fokotsa boroko le ho ntlafatsa boroko.

Kakaretso ea Insomnia

Insomnia ke bothata bo tloaelehileng ba kliniki bo nang le litšusumetso tse ngata ho batho ka bomong le sechabeng. Hangata batho ba nang le bothata ba ho hlobaela ba na le bothata ba ho qala kapa ho boloka boroko, 'me litlamorao tsa mots'eare li kenyelletsa ho tepella, ho se tsotelle le mathata a sekolo kapa mosebetsi. Boholo ba motho e mong o bile le boroko ba nakoana bo amanang le khatello ea maikutlo, bokuli kapa liphetoho tsa kemiso, empa 10-20% ea batho ba na le ho hlobaela ho sa feleng — ke hore, bothata bo phehellang ba ho robala ho feta bosiu bo fetang 3 beke le beke (84, 85). Batho ba nang le ho hloka boroko khafetsa ba na le mokhathala oa mots'eare, ho hloka thabo le ho phela bophelo bo fokolang ho isa tekanyong e le 'ngoe ha ba bapisoa le batho ba nang le mathata a pelo le khatello ea maikutlo (86). Batho ba nang le bothata ba ho hloka boroko ba boetse ba fokotse tlhahiso, litheko tse phahameng tsa mosebetsi o haellang, le kotsi e kholo ea ho ba le khatello ea maikutlo kapa tlhekefetso ea lithethefatsi (87, 88). Ho 1995, litšenyehelo tse tobileng tse hlahisoang ke ho hloka boroko United States li ne li hakanyetsoa ho $ 14 bilione ka selemo, ka $ 2 billion e sebelisitsoeng ho meriana (89), mme litšenyehelo hona joale li phahame haholo.

Ho hloka boroko ke bokuli boo ho bona motho a nang le tšekamelo ea ho robala habonolo, mme mabaka a fapaneng a ka mpefatsa boroko (90). Ho hloka boroko ho atile haholo ho basali le batho ba baholo ba baholo mme ho atile ho batho ba nang le khatello ea maikutlo, matšoenyeho, 'dementia, tlhekefetso ea lithethefatsi le mafu a mang a kelello. Boitšoaro bo bobe ba ho hloka boroko joalo ka nako ea ho robala ntle le tšebeliso ea nako e telele, tšebeliso e boima ea k'hafeine le ho itšepa joala hangata ho kenya letsoho. Ho hloka boroko ho boetse ho hlaha le mathata a sitisang boroko bo kang ho opeloa, ho koaleha boroko, ho phutholoha maoto le mathata a morethetho o mong le o mong moo nako ea kahare ea 'mele e sa tsamaelaneng le nako ea ho robala. Nako le nako, ho hloka boroko ha ho na sesosa se totobetseng sa bongaka kapa kelello 'me ho nkoa e le ho hloka boroko ka sehloohong. Kahoo lingaka tse ngata li qala pele ho phekola khatello ea maikutlo ea mokuli, boits'oaro bo hanyetsang, kapa lintho tse ling tse mpe (91), empa mekhoa ena ka linako tse ling ha e lekane kapa ha e na thuso, 'me bakuli ba bangata ba rua molemo ho litlhare tse khothalletsang boroko.

Litlhare tsa Hona joale tsa Insomnia

Hangata lingaka li phekola ho hloka boroko ka benzodiazepine receptor agonists (BzRAs), bao e leng li-modulators tse ntle tsa GABA_A ho supa seo se thibela ts'ebetso ea methapo e mengata. Nonbenzo-diazepines (mohlala, zolpidem, zaleplon) e fapana ka sebopeho ho tsoa ho li-benzodiazepines tsa moetlo (mohlala, lorazepam, diazepam), 'me ka ho khetheha ba tlama α₁ subunit ea GABA_A receptor. Ha ba tsebe hore na ba khothaletsa boroko joang, empa ba ka ntlafatsa boiketlo ba GABAergic ba li-neurons tse ntlafatsang le lefats'e ka bophara ho fokotsa ts'ebetso ea cortical. Li-BzRA hangata li potlakisa ho qala ho robala, ho fokotsa palo ea batho ba tsosoang boroko, 'me ho ka eketsa palo ea boroko ka botlalo. Lithuto tse 'maloa li boetse li bonts'itse ntlafatso ea tlhokomeliso ea mots'eare le ho phela hantle (92). Ho mamella mamello ho li-BzRAs ha ho sa tloaeleha, 'me liphuputso tse peli tsa nonbenzodiazepines li bonts'itse hantle ho fihlela likhoeling tsa 6 (92, 93).

Li-antidepressants tsa Sedating tse kang trazodone, amitriptyline, le doxepin li boetse li tsebahala ka ho phekola ho hloka boroko, mohlomong hobane li ka ntlafatsa khatello ea maikutlo mme li ka ba le monyetla o fokolang oa ho baka mamello le ho ikemela. Hore na lithethefatsi tsena li khothaletsa boroko joang ha li utloisisoe hantle, empa li ka etsa joalo ka ho thibela litlamorao tsa li-neurotransmitters tse kang serotonin, histamine, norepinephrine le acetylcholine. Le ha li-antidepressants li le har'a li-hypnotics tse tummeng, ha ho na lipatlisiso tse fokolang tsa bongaka mabapi le katleho ea tsona le polokeho ea boroko.94).

Ho sebelisoa meriana e meng e mengata ho phekola ho hloka boroko. Melatonin le ramatonin agonist ramelteon li sebetsa hantle ka tsela e ntlafatsang ho qala ho robala ebile li na le litla-morao tse fokolang ntle le ho tšoaroa ke hlooho ka linako tse ling.95). Ramelteon ha e-so ka e laeloa hohle kamoo ho neng ho lebelletsoe, mohlomong hobane ntlafatso ea boroko e itekanetse mme bakuli ha ba na le ts'usumetso e matla e fuoang ke BzRA. Li-antipsychotic tse kang olanzapine li ka hohela, empa li na le litlamorao tse ngata. The antihistamine diphenhydramine e tsebahala ho lisebelisoa tsa ho robala tse kahare ho mothetsi, empa joalo ka li-antidepressants, liphuputso tse 'maloa li sebetsane le katleho ea tleliniki le polokeho ea meriana ena le e meng ea khale.

Meeli ea Hypnotics ea Hona joale

Lithethefatsi tse ngata tse sebelisoang bakeng sa kalafo ea ho hloka boroko alter neurotransication ho lits'ebetso tse akaretsang tsa GABA, monoaminergic, le cholinergic, ka hona taba ea hore meriana ena e ka hlahisa mefuta e fapaneng ea litlamorao ha e makatse (Lethathamo 1). GABA ke "neurotransmitter" ea mantlha bokong, 'me e ama tsamaiso e' ngoe le e 'ngoe ea boitšoaro, ho kenyelletsa le tse laolang taolo ea kelello, taolo, botsitso le maikutlo. Li-BzRA hangata li mamelleha hantle, empa ho sisinyeha le ho fifala kelellong hoseng ho ka ba boima, haholo-holo ka basebeletsi ba nkang nako e telele. Nako le nako, bakuli ba ka ba le amnesia bakeng sa liketsahalo tse potileng nako ea dosing, mme hangata, li-BzRA li ka lebisa ho ho robala tseleng le boits'oaro bo tšoanang. Kamora hore BzRA e emisoe, ho hlobaela ho ka robala bosiu bo le bong kapa a mabeli ho ka hlaha, haholoholo ka lithethefatsi tse nkang nakoana. Ho sithabela maikutlo ha khafetsa ha se ho tšoenyeha ho tloaelehileng ka litekanyetso tse tloaelehileng, empa lintho tsena tse ka fokolisang boroko bo ka mpefatsa boroko ba ho robala. Ho batho ba baholo ba baholo, ho oa, ho tsoa likotsi le pherekano li atile haholo ho BzRAs le antidepressants (96, 97). Ho tepella le ho hlekefetsoa ha li-BzRA e ka ba ntho e tšoenyang, haholo ho bakuli ba nang le nalane ea tlhekefetso ea lithethefatsi (98, 99).

 

Lethathamo 1

Litholoana tse mpe tsa hypnotics tse tloaelehileng le litlamorao tse ka bakoang ke bahanyetsi ba orexin. Litlamorao tsa lithethefatsi tse tloaelehileng li ngotsoe hantle, empa ha ho tsejoe ka litla-morao tsa bakuli ba orexin. Litla-morao tse kang ho nyefoloa ha hoseng ...

Lingaka tse ling li nka li-antidepressant li sireletsehile ho feta li-BzRA, empa ka kakaretso, litlamorao li atile haholo le tsa pele. Joalo ka li-BzRA, litla-morao li ka kenyelletsa sedation ea mots'eare le pherekano. Li-antidepressants tse nang le thepa ea anticholinergic li ka baka molomo o omileng kapa ho bolokoa ha urine, 'me tse thibelang ho hlaha ha noradrenergic ka linako tse ling li baka hypotension ea orthostatic. Ho phahamisa boima ba 'mele le arrhythmias le tsona ke lintho tse amehileng. Li-antipsychotic li ka hlahisa hypotension, boima ba 'mele, le litlamorao tsa extrapyramidal,' me li-antihistamines li ka baka sedation e telele, ho sitoa ho tseba lintho hantle, le ho nona.

Hobane tsamaiso ea orexin haholo-holo e khothaletsa batho ba tsosang takatso, bahanyetsi ba orexin ba na le monyetla oa ho khothaletsa boroko le ho baka litla-morao tse fokolang. Ho tepella maikutlo le tlhekefetso ha ea lokela ho ba taba e sa tšoenyeheng, kaha lithuto tsa liphoofolo li bontšitse hore bahanyetsi ba orexin ba hlile ba fokotsa ho batla lithethefatsi (69, 100-102). Ho ts'oaroa le ho oa ha ea lokela ho ba bothata, hobane ha ho na bopaki ba hore tsamaiso ea orexin e ama botsali kapa gait ka kotloloho. Liphetho tsa overdose ha ea lokela ho ba le taba e ngata, hobane bahanyetsi ba orexin ha baa lokela ho sithabela haholo ho phefumoloha kapa ho ama khatello ea mali. Litla-morao tse ka bakoang ke ho hanyetsa li-orexin, ho kenyelletsa le disinhibition ea boroko ba REM, li tšohloa ka tlase, empa ka kakaretso, bafuputsi ba bangata ba lebelletse hore lithethefatsi tsena li lokela ho khothaletsa ho robala ntle le litlamorao tse ngata tse kopaneng le meriana ea hona joale. Hape, hobane bahanyetsi ba orexin ba na le mokhoa oa ts'ebetso oa ho sebetsa, ba na le monyetla oa ho ntlafatsa ho hloka boroko ho bakuli ba fumaneng basebeletsi ba bang ba sa sebetse. Lithuto tsa bongaka tse seng li ntse li tsoela pele li lokela ho hlalosa hantle melemo le meeli ea bahanyetsi ba li-orexin receptor antagonists.

Pharmacology ea Preclinical

Nakoana ka mor'a hore ho fumanoe litlamorao, GlaxoSmithKline (GSK) e qalile ho nts'etsapele bahanyetsi, ho kenyeletsoa le lihokahanyo tsa heterocyclic urea.108-110). Har'a tsena, OBNUMXR antagonist SB-1 e ithutile haholo hobane e na le pharmacokinetics e ntle ebile e fumaneha habonolo (Lethathamo 2). Kamano ea eona ea OX1R e phahame ka makhetlo a 50 ho feta ea OX2R, empa tse ling tsa lithuto tsa vivo tse sebelisang litekanyetso tse phahameng li lokela ho talingoa ka hloko hobane litekanyetso tseo li ka thibela li-receptor ka bobeli. Ntle le moo, GSK e hlalositse bahanyetsi ba bang ba khethang, ho kenyeletsoa SB-408124 le SB-410220, tse nang le khetho e ~ 50 ea batho OX1R lithutong tse tlamang, le SB-674042, e leng> 100-fold selective (108, 109, 111, 112). Ho 2009, GSK e phatlalalitse hore SB-649868, mohanyetsi oa OX1R / OX2R, o khothalelitse boroko ba REM le ba eseng REM ka likhoto le marmosets (113). Lintlha tse tebileng tsa precinical pharmacology ka molek'huleng ena ha li e-so phatlalatsoe, empa SB-649868 e kentse lithuto tsa tliliniki ea Phase II (114).

 

Lethathamo 2

Meralo ea ba bang ba bohanyetsi ba mantlha ba orexin le li-affinities tsa bona bakeng sa li-receptors tsa OX1 le OX2

Ho 2007, Actelion e phatlalalitse tlhaloso e qaqileng ea almorexant (ACT-078573), mohanyetsi ea matla oa orexin receptorist, ea nang le IC₅₀ boleng ba 13 nM le 8 nM ho li-assays tse thehiloeng ho sele bakeng sa OX1R ea motho le OX2R, ka ho latellana (103, 107). Almorexant e bonahala e le mohanyetsi oa tlholisano oa OX1R le mohanyetsi ea sa lumellaneng le OX2R (115). E ikhethile haholo ka tumellano e nyane bakeng sa litefiso tse ling tsa 90 tse fetang; ke ~ 99% protheine e tlameletsoeng ho rat le motho; e na le bioavailability e tlase e nang le tekanyetso ea molomo ho likhoto (8-34%) le lintja (18-49%); mme e kenella bokong hantle. Almorexant e na le ho monya hantle ho lintja (T_{, max} = 0.5-2 h) e felisang halofo ea bophelo ba 8-9 h. Tsamaiso ea molomo ea almorexant ho litekanyetso tsa rats-ka ho iketelletsa boroko e se nang REM le REM ha e fanoa nakong ea ts'ebetso, ntle le tahlehelo ea ts'ebetso ho feta bosiu ba 5 bosiu ba kalafo (107, 116). Ka lehlakoreng le leng, likhoto tse tšoaroang ka zolpidem li ne li na le boroko bo eketsehileng boo eseng ba REM empa bo ne bo le tlase ho robala ka REM mme bo bile le mamello ho feta masiu a 'maloa a dosing (107). Leha ho le joalo, ha almorexant e fanoa nakong ea phomolo, e bile le phello e fokolang ho boroko, ho fana ka maikutlo a hore moriana o sebetsa hantle haholo ha orexin tone le wake drive li le holimo (107, 117) (empa hape bona Reference 112). Litholoana tsa almorexant molumo oa molumo oa boikemelo li nyane; ho likhoto tse lumelletsoeng ho hlahloba, e fokotse tekanyo ea pelo le khatello ea mali hanyane, empa e bile le phello e nyane nakong ea phomolo (75). Ho lintja, e fokotsa ts'ebetso ea locomotor ntle le litlamorao tse kholo tsa mocheso oa 'mele, khatello ea mali, kapa sekhahla sa pelo (107). Ka pharmacology ena e ntle le litlamorao tse matla tsa ho khothaletsa boroko liphoofolong, Actelion o ile a latela lithuto tsa kliniki tsa almorexant, tse hlalositsoeng ka tlase.

Merck o thehile mefuta e mengata ea bahanyetsi ba li-orexin receptor ka lihlopha tse 'maloa tse arohaneng tsa sebopeho (104, 105, 118, 119). DORA-1 ke mohanyetsi ea matla le o mong oa li-orexin receptor o tsoang letotong la proline bis-amide (120). E na le thepa e ntle ea pharmacological ho liphoofolo, e na le tšebelisano e phahameng bakeng sa bobeli ba OX1R le OX2R, e na le phello e ntle ea bokong, hape e fumaneha ka mokhoa o itekanetseng litloaelong. Ka vivo, DORA-1 e thibela keketseho ea mofuta oa boitšisinyo o susumetsoang ke orexin le lethal dose-ka tsela e ts'epahalang e khothaletsa ho robala ho litoeba (121). Mofani e mong oa semolao oa moea orexin receptor antagonist, DORA-5, o tsoa ho N, NScaffold e khethiloeng-1,4-diazepane (118, 122). K'homphieutha ena e na le tšusumetso e matla litlamong tse thehiloeng ho sele 'me e sebetsana le ho thunya ha neuron-A-e hlohlellelitseng neuronal ho thunya ha "rat dorsal raphe neurons". DORA-5 e boetse e fokotsitse tšebetso ea lenaka la rat le ho fokotsa ka nepo mafolofolo a itseng ha a ntse a eketsa boroko ba REM le bao eseng ba REM (122). MK-4305 ke mohanyetsi ea matla le ea khethiloeng oa orexin receptor o tsoang lethathamong la diazepane, a bonts'a mohanyetsi oa nanomolar ho li-assays tsa seleng (OX1R IC₅₀ = 50 nM, OX2R IC₅₀ = 56 nM) le> khetho ea makhetlo a 6,000 khahlano le sehlopha sa li-receptor le li-enzyme tse 170. Motsoako ona ha o fumanehe ka molomo, o na le phunyeletso e ntle ea boko, mme o bonts'a ho amohela orexin receptor bokong ba rat. Lithutong tsa boroko ba litoeba, MK-4305 e thehiloe ka tekano ho fokotsa ts'ehetso e matla le ho eketsa boroko ba REM le bo seng ba REM ha e sebelisoa ka molomo ho 10, 30, le 100 mg kg−¹. E tšehelitsoe ke liphetho tsena tse khothatsang tsa tlhahlobo ea pele, MK-4305 e se e hatetse pele kholisong ea bongaka (123).

Hoffmann – La Roche e hlahisitse mohanyetsi ea matla oa OX2R ea tsejoang e le EMPA ea bonts'ang> khetho e menahaneng ka makhetlo a 900 ho tlama OX2R ho feta OX1R (124). K'homphieutha ena e fokotsa phokotso ea boithatelo 'me e thibela keketseho ea tšusumetso e hlahisoang ke sekhechana sa orexin-B, empa litlamorao tsa eona tsa ho phahamisa boroko ha li so hlahisoe.

Bafuputsi ba Johnson & Johnson ba hlalositse li-dioxanes tse 4-phenyl- [1,3] tse nkeloang sebaka ka> khetho ea makhetlo a 800 bakeng sa ho loants'a OX2R (125). Sehlopha sena se sa tsoa tlaleha hore JNJ-10397049 (mohanyetsi oa OX2R) le almorexant li eketsehile haholo boroko ba REM le bao e seng REM le ho fokotsa tsoho e sebetsang (112). Ka lehlakoreng le leng, mohanyetsi oa OX1R SB-408124 ha a na litlamorao tse matla tsa ho robala ho litoeba, a ts'ehetsa tlhokomeliso e akaretsang ea hore litlamorao tsa ts'ebetso ea li-orexins li tsamaisoa haholo-holo ke OX2R kapa motsoako oa OX1R le OX2R.

Likhamphani tse ling li lemohile bahanyetsi ba orexin, empa lintlha tse fumanehang li lekanyelitsoe feela ho sebopeho sa vitro (bona Likarabo 105 'me 106 bakeng sa litlhahlobo). Setsi sa Patlisiso sa Banyu Tsukuba se hlalositse letoto la metsoako ea tetrahydroisoquinoline amide e nang le khetho ea makhetlo a 45 ho isa ho 250 bakeng sa OX2R ho feta OX1R, e nang le mokelikeli o motle le boikhethelo khahlano le sehlopha sa> 50 receptors le enzyme (126). Sanofi-Aventis e hlahisitse li-patent bakeng sa bahanyetsi ba 'maloa ba khethiloeng ho tloha 20- ho ea 600-fold ea OX1R, hammoho le bahanyetsi ba leka-lekaneng ba nang le 5- ho 20-fold selecaction bakeng sa OX1R holim' a OX2R. Biovitrum e tlalehiloe likhomphutha tse nang le liphaephe ho tloha 30 nM ho 2 mM ea OX1R.

Clinical Pharmacology

Ha ho na bahanyetsi ba li-orexin receptor ba kentsoeng bakeng sa tumello ke mekhatlo ea tsamaiso, empa Actelion, GlaxoSmithKline, le Merck ba tlalehetse tlhahlobo e 'ngoe le e' ngoe ea mafolofolo tlhabollong ea li-orexin receptor antagonists bakeng sa ho hloka boroko.

Actelion o hlahisitse data ea Phase I e khothatsang mabapi le litlamorao tse khothaletsang boroko ba almorexant ho 2007 (107). Ho banna ba phetseng hantle, bahlankana, almorexant e ne e mamelletsoe hantle ho fihlela 1000 mg ntle le liketsahalo tse mpe tse mpe (107). Seteishene se ile sa bontša ho amoheloa ka potlako (T_{, max} = 1.0 ho ea lihora tsa 2.3) le keketseho e lekanang ea ho pepeseha ho ipapisitseng le litekanyetso tsa plasma AUC ka tekanyetso ho tloha 100 mg ho 1000 mg. Almorexant o ne a e-na le li-kinetics tse felisang biphasic, ka halofo ea bophelo ba 6.1 ho isa lihora tsa 19.0. Litekanyetso tsa 200 ho fihlela 1000 mg haholo li fokolitse matla a morao ho kena boroko boo e seng ba REM, ho eketsa palo ea boroko, le ho eketsa maikutlo a ho robala ka mokhoa o hlakileng (107).

Thutong ea Bobeli, ho na le liphuputso tse peli tse sa boneng bakuli ba 147 ba nang le bothata ba ho hlobaela ba mantlha, 200 kapa 400 mg almorexant e fanoeng pele ho nako ea ho robala, ka ho eketseha ha ts'ebetso ea boroko ho tloha basement ea ~ 75% ho ea ho ~ 85% ea bosiu.127). Litholoana tse tšoanang li boetse li na le tloaelo ea ho ntlafatsa tsoho kamora ho robala ka 35-55 metsotso le ho khutsufatsa boroko bo phehellang. Litakatso tse kenelletseng tsa boroko ba ho robala le palo ea boroko le tsona li ntlafalitsoe. Joalokaha ho ne ho lebelletsoe, latency ea ho kena boroko ba REM e ile ea khutsisoa hanyane, mme palo ea boroko ba REM e ile ea eketseha hanyane. Ho tloha 2008, Actelion o ntse a etsa lithuto tsa Phase III le Almorexant ho tekanyetso ea 100 mg le 200 mg.

GlaxoSmithKline e tlaleha hore tekanyetso ea bona ea OX1R / OX2R SB-649868-ka tsela e itšetlehileng e ile ea eketsa boroko ho 10 le 30 mg ka mohlala oa ho hloka boroko moo boroko ba baithaopi ba phetseng hantle bo neng bo sitisoa ke lerata (113). Setsi sena se boetse se bonahala se haelloa ke ts'usumetso ea mesaletsa ea hoseng. Boithuto ho bakuli ba hlokang boroko bo bontšitse hore SB-649868 e fokotsitse latency ho robala le ho tsoha ka mor'a ho robala, le nako e eketsehileng ea ho robala (114). Ka lebaka la chefo e sa reroang ea preclinical, nts'etsopele ea SB-649868 e kentsoe qetellong ea 2007 empa hajoale e thathamisitsoe e le ea nts'etsopele ea Phase II (128). GSK e kopantsoeng le Actelion ho 2008 ho nts'etsapele almorexant bakeng sa ho hlobaela.

MK-4305 ke mohanyetsi oa OX1R / OX2R o nts'etsopele ke Merck bakeng sa kalafo ea ho hloka boroko. Seteishene sena se na le thepa e ntle ea pharmacokinetic le katleho e ntle ea preclinical (123). Ho 2009, Merck o ile a etsa lithuto tsa Phase II le bakuli ba hlokang boroko, 'me ka 4305, ba phatlalatsa hore MK-2010 e kene katolosong ea Phase III.

Lintlafatso tsena ho qala le ho boloka boroko le batho ba loantšanang le orexin li fana ka tšehetso ea bohlokoa bakeng sa nts'etsopele ea lingaka tsa orexin e le kalafo e ncha ea ho hloka boroko. Lik'hemik'hale tse 'maloa tse ikemetseng tse ikemetseng li bonts'a litlamorao tse ts'oanang, ka likhahla tsa ho robala ntle le REM le REM tse fapaneng le sebopeho se bonoang ka hypnotics e tloaelehileng.

Liphello Tse Bohloko

Ho fihlela joale, tlhaiso-leseling e fumaneha phatlalatsa ka litlamorao tse mpe tsa bahanyetsi ba orexin, empa motheong oa bopaki bo fumanehang le litlamorao tse boletsoeng esale pele tsa orexin blockade, motho a ka lebella hore bahanyetsi ba orexin ba tla ba le profil e ntle ea ketsahalo ho feta li-hypnotics tse teng hona joale (Lethathamo 1). Barekisi ba Orexin ba kanna ba ba le litekanyetso tsa bona tse ikhethang, 'me ho hlokahala lintlha tse ling tsa kliniki. Leha ho le joalo, ho fapana le li-BzRA, li lokela ho ba le monyetla o fokolang oa ho hlekefetsoa kapa ho hloka botsitso, mme ho fapana le li-antidepressants, ha li na monyetla oa ho baka litlamorao tse ikemetseng joalo ka orthostasis.

Ho robala hoseng kapa mots'eare e kanna ea eba taba ea lithethefatsi tse tsoelang pele ho thibela sign ea orexin ha e tsoha. Mohlomong, boroko bona bo bontša ka tsela e fapaneng le kamoo bo hlahisang li-BzRAs hobane batho ba nang le bothata ba ho hlonama hangata ba ikutloa ba falimehile ha ba tsoha ebe ba robala hamorao ka letsatsi. Kahoo, litekong tsa bongaka, ho tla ba bohlokoa ho lekola boroko nakong ea letsatsi lohle, eseng feela hoseng.

Ho fapana le lits'oants'o tse ling, bahanyetsi ba orexin ba ka baka ho robala ha REM joalo ka ha ho kopane le narcolepsy. Ho tsitsipana ha kelello le ho holofala ho robala ho ka etsahala nakong ea ha motho a robala kapa a tsoha, leha a sa tlaleheloa. Ka kakaretso, matšoao ana a ferekanya empa a feta kapele, mme a lokela ho laoleha ka thuto ea mokuli le phokotso ea litekanyetso. Monyetla oa cataplexy ke tšoenyeho e kholo hobane ho oa ka tšohanyetso ho ka baka likotsi, leha ho le joalo batho ba nang le narcolepsy ka seoelo ba na le cataplexy nakong ea bona ea boroko, 'me ha ho cataplexy e ileng ea bonoa le almorexant ho likhoto, lintja le batho ho sa tsotellehe maemo a phahameng a receptor blockade (107). Leha ho le joalo, lithuto tsena li kanna tsa pepeta tloaelo ea ho batla ho bua ka taba ea hore motho o batla a le mongata hobane hangata e bakoa ke maikutlo a matla (mohlala, ho tšeha metlae e kholo) mme ho thata ho hohela ka lab (57, 129). Ntle le moo, liphoofolo le lithuto li ne li lumelloa ho robala lithutong tse ngata, tse neng li ka sitisa tloaelo efe kapa efe ea ho tšoaroa ke bokhopo. Ho ka etsahalang, cataplexy e tla ba ntho e tšoenyang feela maemong a sa tloaelehang e sa amaneng le ts'ebeliso ea bongaka e reretsoeng, joalo ka ha mokuli a falimehile a bile a le botsoalle kamora ho nka tekanyo e phahameng ea mohanyetsi oa orexin.

Ha ho nahanoa hore li-orexin li khothalletsa ho tsoha le ho hatella boroko ba REM, motho a ka fumana e le ntho e makatsang le ho makatsa hore batho ba nang le lefu la boroko ba robetse ka ho lekana boroko, ho robala ka nako ea boroko e seng ea REM, le ho sisinyeha nakong ea boroko ba REM bo bitsoang REM boroko bo sitisang boroko.130). Mohlomong, matšoao ana ke phello ea khaello ea orexin e sa feleng kapa ho lemala ha li-neuron ntle le tse hlahisang li-orexin. Kaha matšoao ana ho thata ho a hlalosa le mehlala ea hona joale, ho bolela esale pele hore na ho ka etsahala hore ebe ho na le bahanyetsi ba orexin. Leha ho le joalo, lintja, ho fetella le ho feta ha litho tsa maoto le matsoho ha li robala (107), 'me lithuto tsa tliliniki li lokela ho lekola ho sisinyeha kapa ho sitisoa ha boroko bo bong.

Ho supa ha Orexin ho bonahala ho ntlafatsa ts'ebetso litseleng tsa mesolimbic tse laolang moputso le tšusumetso, mme ts'ebetso e fokotsehileng tsamaisong ena e ka mpefatsa boemo ba maikutlo kapa khothatso. Batho ba nang le lefu la ho hlonama ba ka ba le khatello e phahameng ea khatello ea maikutlo (131), leha ho sa tsejoe haeba sena e le litlamorao tse tobileng tsa ho saena hoa orexin kapa karabelo phephetsong ea ho ba le bokuli bo sa foleng. Ntle le moo, ho robala hantle ho bakuli ba nang le khatello ea maikutlo ho ka ntlafatsa maikutlo. Joalokaha bakuli ba bangata ba nang le bothata ba ho hlobaela ba na le khatello ea maikutlo, baoki ba lokela ho shebella liphetoho tse bang teng moong.

Li-BzRA li ka sithabetsa ho hema le ho koaleha moea ka nakoana borokong kapa lefu le matla la matšoafo, 'me ho fetelletsa ho ka bolaea, haholo ha e sebelisoa hammoho le joala kapa lintho tse ling tse ka o thusang. Ha litoeba tsa orexin tsa ho kokota li na le moea o lekaneng oa moea o lekaneng (132), ho bonahala eka ha ho na monyetla oa hore bahanyetsi ba orexin ba ka fokotsa haholo drive ea phefumoloho. Leha ho le joalo, ba ka fokotsa karabelo ho hypercarbia. Maemo a phahameng a CO₂ eketsa lebelo la phefumoloho le bophahamo ba lefatše, 'me bahanyetsi ba orexin ba ka ts'oenya karabelo ena, haholo-holo nakong ea ho tsoha (132, 133). Kahoo ho ka ba bohlale ho hlahlobisisa litla-morao tsa orexin ho bakuli ba nang le hypercarbia, joalo ka batho ba nang le lefu le tebileng la 'mele le amanang le pulmonary (COPD) kapa bofokoli ba mesifa ea ho hema.

Hore na orexin e ama takatso ea lijo kapa metabolism ho batho e lula e sa tsejoe, empa batho le litoeba tse nang le narcolepsy li na le boima bo bongata ho sa tsotelehe ho bonahala ho ja tse fokolang ho feta tse tloaelehileng (35, 80, 81). Kahoo khaello ea orexin e ka fokotsa tekanyo ea metabolic, mme bahanyetsi ba orexin ba ka khothaletsa ho nona ka boima ba 'mele haeba e fanoa nako e telele. Ka ts'ebetso, lihanyetsi tsa orexin li tla fanoa haholo bosiu, 'me ho tšoaea ho tloaelehileng ha orexin motšehare ho lokela ho fokotsa ho fokotsoa ha metabolism kapa tlala bosiu.

Li-BzRA le li-antidepressant tse thetsang li ka hlahisa li-gait tse sa tsitsang, ho tsekela le ho oela, empa tsena ha li na monyetla oa ho ameha ka bahanyetsi ba orexin kaha cerebellum le vestibular nuclei ha e hlile e haelloa ke li-fibre le li-receptor (7, 14). Litoeba tsa Orexin tsa ho kokota li matha ka lebelo le tloaelehileng (51, 83), le likhoto tse tšoaroang ka EMPA kapa ka alingoxant hantle moloreng124, 134). Lithuto tsa pilot tsa almorexant bathong li bontšitse keketseho e nyane feela ho ho ruruha ha mmele 1-3 h kamora ho hlaka (135), ka hona ho bonahala eka ha ho na monyetla oa hore bahanyetsi ba orexin ba tla eketsa kotsi ea ho oa.

Barekisi ba Orexin ba kanna ba qojoa ho bakuli ba nang le lefu la mokokotlo hobane ba ka mpefatsa mats'oao a mang a bakuli. Lik'hemik'hale tsena li kanna tsa ba le kotsi e kholo ea ho hlahisa litla-morao tsa narcolepsy mots'eare matsatsing a mang a ts'enyo eo ho eona likotsi tsa methapo ea kutlo li lemalang, joalo ka lefu la Parkinson le likotsi tse mpe tsa boko bo bohloko (136-138). Kahoo ho bakuli bao, lingaka li ka nahana ho qala kalafo ka tekanyetso e tlase.

Bafuputsi ba bang ba belaetse hore na ho na le bohlokoa ba ho hlahisa litlamorao tsa boits'oaro bo tšoanang le narcolepsy (139), empa ka kakaretso, ho bonahala eka bahanyetsi ba orexin ba lokela ho khothaletsa ho robala ka litla-morao tse fokolang le tse seng kotsi ho feta li-hypnotics tse ngata tsa hona joale. Liteko tse sa khaotseng tsa kliniki li shebelletse matšoao a amanang le ho robala ha REM, 'me ho shebella boroko bo arohaneng, ho sisinyeha nakong ea boroko le ho tepella maikutlo le ho feta ho tla ba bohlokoa. Ho ts'oaroa ha motšehare ha hoa lokela ho ba ho ameha haholo ka likhomphutha tse nang le kinetics e ntle e lumellang orexin e tloaelehileng ho saena motšehare.

Ho ngoloa ha tekolo ena ho tšehelitsoe ke Institutes tsa naha tsa lithuso tsa NS055367 le HL095491. Bangoli ba leboha litlhaloso tse nahannoeng ke T. Mochizuki, JK Walsh, le JJ Renger mabapi le mongolo.

• TMN
• tuberomammillary nucleus
• VTA
• sebaka sa ventral tegmental
• DMH
• dorsomedial nucleus ea hypothalamus
• SETSOHA SEGOLO
• G protheine-e laoloang khubung e nchafatsang
• NMDA
• N-methyl-D-motsoana
• Ho potlaka ha leihlo (REM) boroko
• sethala sa boroko se tsebahalang ka litoro tse hlakileng, ts'ebetso ea methapo ea methapo, ho sisinyeha ha mahlo le ho holofala ha mesifa ea masapo
• Boroko bo senang REM
• sethala sa ho robala ka mehopolo e sa hlakileng kapa ho se tsebe letho, le ho ikoetlisa butle butle
• CSF
• se nang le lero le leholo
• Hypnagogic hallucinations
• litoro tse kang litoro ho potoloha ho qala kapa ho fela ha boroko
• Ho robala litho tse amanang le boroko
• ho sitoa ho tsamaea holim'a ho tsoha kapa ha o ts'oha
• Cataplexy
• ho shoa litho ka tsela e sa reroang kapa ho fella ka metsotso e seng mekae ho fihlela metsotso e seng mekae; hangata e susumetsoa ke maikutlo a matla a kang ho tšeha
• Senomotor sensitization
• litekanyetso tse eketsehileng tsa karabelo ho arabela ka tekanyetso e tšoanang ea lithethefatsi
• Ho hloka boroko
• ho hloka boroko ho sa hlahiseng lebaka le hlakileng la kelello kapa la bongaka
• Li-BzRA
• benzodiazepine receptor agonists
• Ho robala hantle
• liperesente tsa nako ea betheng ba robala
• Tsoha kamora ho robala
• nako eo u e qetang u falimehile kamora ho robala

TLHOKOMELISO SEBETE

TES e rerile mabapi le bahanyetsi ba orexin bakeng sa Merck & Co, GlaxoSmithKline (GSK), Hoffmann – La Roche le Actelion. CJW ke mosebeletsi oa Merck Sharp & Dohme Corp. mme o na le setoko ebile o na le likhetho tsa setoko k'hamphaning.