I-Orexin1 i-receptor antagonists ngokuziphatha okunyanisekileyo kunye nokuxhalabisa: ukusetyenziswa kwonyango (2014)

Front Neurosci. I-2014; I-8: 26.

PMCID: PMC3923148

Eli nqaku liye khankanywe ngu amanye amanqaku kwi-PMC.

Yiya e:

Abstract

Kwiminyaka elishumi elinesihlanu emva kokufunyaniswa kwe-hypocretin/orexin, kuye kwaqokelelwa ubungqina obuninzi obuxhasa indima yayo ebalulekileyo ekumodareyithweni kwemisebenzi emininzi elawula umzimba. Ngelixa amanqanaba ancitshisiweyo e-hypocretin/orexin aqale anxulunyaniswa ne-narcolepsy, amanqanaba awonyukayo adityaniswa kwiminyaka yakutshanje ukuya kwimeko ye-pathological ye-hypervigilance kwaye, ngakumbi, ukuphuthelwa. Ukugcwaliswa kwi-FDA ye-double-activity orexin receptor antagonist (DORA) suvorexant yesalathiso sokuphuthelwa kuqinisekisa ngakumbi ukomelela kobo bungqina. Nangona kunjalo, njengoko uphapheme olugqithisileyo lukwayinto eqhelekileyo yonxunguphalo kunye neziqendu zokoyika, kunye nokuziyeka kunye nokunqwenela ukuphazamiseka kokusetyenziswa gwenxa kweziyobisi. Kolu hlaziyo sixoxa ngokufutshane ngobungqina obuxhasa ukuphuhliswa kwe-hypocretin / orexin receptor 1 (OX1) abachasayo kwezi zibonakaliso. Amalingo asebenzisa umchasi we-OX1 u-SB-334867 kunye neempuku eziguqukayo zibandakanye i-OX1 receptor ekulayini ukubuyiswa okunyanzelekileyo kweziyobisi ezifuna i-ethanol, inikotini, icocaine, i-cannabinoids kunye nemorphine. Ngoku kutshanje, idatha yenziwe nge-noveli ekhethiweyo ye-OX1 abachasi be-GSK1059865 kunye ne-ACT-335827 ekuphenduleni kokuziphatha kunye nentliziyo kwi-stressors kunye ne-panic-inducing agents kwizilwanyana. Ukuqukumbela, ngelixa ulinde idatha ye-pharmacologic ukuba ifumaneke ebantwini, iingozi kunye neenzuzo zokuphuhliswa kwe-OX1 ye-receptor antagonist ye-Binge Eating kunye ne-Anxiety Disorders zixutyushwa.

Internet: umlutha weziyobisi, ukuphinda ubuyele, ukutya kakhulu, ukuziphatha okuphindaphindiweyo, imvakalelo, i-OX1 receptor antagonist, GSK1059865

intshayelelo

I-Hypocretin/orexin yi-hypothalamic neuropeptide equkethe iifom ezimbini, i-A kunye ne-B, equkethe i-33 kunye ne-28 amino acids ngokulandelanayo, kwaye ibophelela kwii-receptors ezimbini ze-G-protein ezidibeneyo, i-OX1 (okanye i-hcrt-1) kunye ne-OX2 (okanye i-hcrt-2) ( de Lecea et al., 1998; Sakurai et al., 1998).

I-hypocretin / i-orexin peptide iveliswa kwindawo encinci ye-neurons ehlala kwindawo ye-dorsomedial-perifornical hypothalamic (DMH / PeF) kunye ne-lateral hypothalamic nucleus (LH). Imicu ye-nerve ene-positive kunye ne-terminals inokufumaneka kwiindawo ezininzi ze-nervous kunye ne-peripheral nervous system, kubandakanya i-vagus nerve, intambo yomgogodla, i-brainstem, i-hypothalamus, i-thalamus, i-limbic system, kunye nemimandla ethile ye-cortical (Peyron et al., 1998; Heinonen et al., 2008). I-OX / hcrt receptors ibonisa ukusabalalisa okwandisiweyo okufanayo (uMarcus et al., 2001), icebisa indima enokubakho ye-hypocretins/orexins njenge-peptides elawulayo kwimisebenzi emininzi eguqukayo kunye ne-limbic elawulwa yinkqubo (Johnson et al., 2012a,b; UMahler et al., 2012; Boutrel et al., 2013; Tsujino kunye noSakurai, 2013).

I-OX1 i-receptor iqulethe i-425 amino acids ngelixa i-OX2 i-receptor iqulethe i-444 amino acids kunye nokulandelelana okufanayo phakathi kwee-receptors ezimbini ze-68% (Sakurai et al., 1998). Ngelixa zombini ii-receptors zidityaniswa ne-Gq-protein, kuphela i-OX1 receptor eyongeziweyo idityaniswa ne-Gs-protein. Ukusetyenziswa kwe-receptor kwandisa amanqanaba e-calcium ye-intracellular ngokusebenzisa i-Gq-exhomekeke kwi-phospholipase C (PLC)-yonyuso lwe-inositol-1,4,5-triphosphate (Lund et al., 2000) kunye ne-diacylglycerol, okubangela ukuba kusebenze i-δ yefom yeprotein kinase C, ekugqibeleni ibandakanye indlela ye-ERK phosphorylation (Ekholm et al., 2007).

I-OX1 kunye ne-OX2 ii-receptors zisasazwa ngokwahlukileyo kwingqondo ye-mammalian (uMarcus et al., 2001), ukuhambelana nokuhanjiswa kwe-hypocretin/orexin terminals. Ubungqina bokwahlula okusebenzayo kwee-receptors ezimbini kutshanje kufunyenwe kusetyenziswa i-pharmacological magnetic resonance imaging (phMRI) kwiigundane. Iziphumo ezisebenzayo ze-amphetamine zahlulwe ngokwahlukileyo ngonyango lwangaphambili kunye ne-OX2 ekhethiweyo ye-receptor antagonist JNJ-1037049 okanye inoveli ye-OX1 receptor antagonist GSK1059865: I-JNJ-1037049 ithintele iimpembelelo ze-amphetamine kunye nemimandla ye-amphetamine kunye neendawo ze-amphetamine kwindawo ye-amphetamine kunye ne-frontal1059865 corteal, i-Glamusal XNUMX, i-GQXNUMX, i-GQXNUMX, i-GXNUMX, i-GSKXNUMX. ukunciphisa ukusebenza kwi-amygdala eyandisiweyo, i-BNST kunye ne-ventral striatum; zonke iindawo zengqondo ezibandakanyekayo kuxinzelelo kunye nokukhuthaza (Gozzi et al., 2011). Lo mahluko kwiimephu ezisebenzayo, kunye nomahluko kwiiprofayili zokuziphatha zixhasa ingqiqo yokuphonononga izalathisi ezahlukeneyo zenoveli yonyango ejolise ngokukhethekileyo kwi-OX1 okanye i-OX2 receptors. Nangona kunjalo, ngelixa indima ye-OX2 receptor ebuthongweni kunye nokuvuswa ixhaswa ngamandla bubungqina obukhoyo bokulinga (Gatfield et al., 2010), amandla okunyanga okuchasayo okukhethiweyo kwe-OX1 receptor kusephantsi kovavanyo (Gotter et al., 2012).

Ukuqonda ngcono ibhayoloji ye-hypocretin/orexin inkqubo ikhuthaze iinkqubo zokufunyanwa kwechiza kwiinkampani ezininzi zamayeza, okukhokelela kuthotho lwamalungelo awodwa omenzi wechiza kunye neekhompawundi ezinokhetho olwahlukileyo kunye. in vitro iimpawu (Faedo et al., 2012; Lebold et al., 2013). Njengoko kubonisiwe ngasentla, ezinye iikhompawundi zazisetyenziswa njengezixhobo ze-pharmacologic zokuphonononga i-OX1- kunye ne-OX2 exhomekeke kwi-neurotransmission. kwi vivo. Ambalwa amakhompawundi aqhutyelwe ngempumelelo ebantwini, ngakumbi i-OX1-OX2 i-receptor antagonist (DORA) almorexant (Hoever et al., 2012), SB-649868 (Bettica et al., 2012), kunye ne-suvorexant (Herring et al., 2012). Kuphela i-suvorexant ihambe ngempumelelo kwiSigaba sesi-3 kwaye yafakwa e-USA njengonyango olutsha lokungalali ngo-2013.

Isixhobo sokuqala se-pharmacological esisetyenziswe njenge-OX1 i-receptor antagonist yayingu-SB-334867 (uJones et al., 2001; Smart et al., 2001). Kutshanje, ezinye iikhompawundi ziye zacetywa: GSK1059865 (Alvaro et al., 2009; Gozzi et al., 2011), 2,5 di-substituted piperidines (Jiang et al., 2012) kunye ne-ACT-335827 (uSteiner et al., 2013).

Kolu phononongo sijongana nobungqina, ubukhulu becala obuqokelelwe ngezixhobo ze-pharmacologic, ngendima ekhethiweyo ye-OX1-mediated neurotransmission ekuziphatheni okunyanzelekileyo, ngakumbi ngokunxulumene nokukhobokisa kunye nokutya kakhulu, kunye nokuxhalaba.

I-Hypocretin/orexin kunye ne-OX1 receptor kwiziyobisi-ezifana kunye nokuziphatha okunyanzelekileyo kokutya.

Iziphumo ezininzi zangaphambi kweklinikhi zibonise ukubandakanyeka kwenkqubo ye-hypocretin/orexin ekuziphatheni okunyanzelekileyo kunye nokuphindaphinda kunye nokulawula ukuziphatha okujoliswe kuko. Uphononongo lwakutsha nje lushwankathela ubungqina obuqokelelwe kumanqaku angaphezu kwekhulu abonisa ukuba inkqubo ye-hypocretin/orexin kwi-lateral hypothalamus (uHarris et al., 2005) ubandakanyeka kumlutha wokuziphatha okufana ne-dysregulations ehambelana nokuvezwa kwe-cocaine, i-amphetamine, i-morphine, i-heroin, inicotine, i-ethanol kunye ne-cannabinoids kwiimpuku (Espana et al., 2011; UMahler et al., 2012; Boutrel et al., 2013; Flores et al., 2013), kunye nokutya kakhulu ukutya okunencasa okunxulumene nokutya ngokutya (Tsujino kunye noSakurai, 2013).

Idatha exhasa ukubandakanyeka kwe-hypocretin/orexin kwiziphumo zeziyobisi ezikhobokisayo yafunyanwa kuqala kwiimpuku ezithwele i-null mutation (KO) ye-hypocretin/orexin peptide, ebonisa iimpawu ezincitshisiweyo zokurhoxa kwi-morphine (Georgescu et al., 2003). Emva koko, indawo enemeko yokungasebenzi kakuhle ekhethwayo yemorphine (uNarita et al., 2006) kunye nenikotini (Plaza-Zabala et al., 2012) yaboniswa kwiimpuku. Kutshanje, izifundo kwiimpuku ze-KO ngokucinywa kwe-OX1 receptor zibonise ukunciphisa i-cocaine kunye ne-cannabinoid self-control kunye nokuvalwa kokubuyiselwa kweziyobisi emva kokuyeka (Hollander et al., 2012; Flores et al., 2013), ebonisa indima ebalulekileyo kwi-OX1 receptors ekulamleni ukubuyiselwa kokufuna iziyobisi.

Kwiintonga ze-SB-334867, umchasi okhethiweyo we-OX1 we-receptor, ukunciphisa uvakalelo, isimilo sokufuna iziyobisi kunye nesifo sokurhoxisa kwiimpuku ezivezwe kwi-ethanol, nicotine, imorphine, kunye ne-cocaine. Ezi kunye nezinye iziphumo zichazwe ngokubanzi kuphononongo lwamva nje (u-Mahler et al., 2012; Boutrel et al., 2013). Okubangela umdla ngakumbi kukuba i-SB-334867 isoloko iyijongela phantsi indlela yokuziphatha enyanzelekileyo eyayanyaniswa nokubuyiselwa kokufuna iziyobisi, okubangelwa luxinezeleko oluqatha okanye imiqondiso eyayanyaniswa ngaphambili nokusetyenziswa kweziyobisi, into ebonwe kwi-ethanol, inikotini, i-cocaine, i-cannabinoids kunye ne-morphine.

Kutshanje, i-OX1 echasene ne-receptor ekhethiweyo GSK1059865 (5-bromo-N-[(2S,5S) -1-(3-fluoro-2-methoxybenzoyl) -5-methylpiperidin-2-yl]methyl-pyridin-2-amine ) ibonakaliswe kwingqokelela ye-GSK (Alvaro et al., 2009). I-GSK1059865 kwidosi ye-25 mg / kg ip (kuqikelelwa ukuba ithathe ngokupheleleyo i-OX1 i-receptors kwingqondo yegundane) iguqule kancinane kuphela ubuthongo be-physiological beegundane, ebonisa umphumo obuthathaka we-hypnotic (Gozzi et al., 2011; Piccoli et al., 2012) kunye nokuqinisekisa umahluko ngokuchasene ne-OX2 receptor blockade (Mieda et al., 2011). Kwelinye icala, kwi-10 kunye ne-30 mg/kg iidosi ze-ip, i-GSK1059865 ichasene kakhulu nefuthe le-cocaine kwindawo ekhethwayo yendawo (Gozzi et al., 2011). Ezi ziphumo zihambelana nendima ecetywayo ye-OX1 receptor antagonism ekhethiweyo ekuthinteleni ukuphinda ufune iziyobisi kodwa ungabangeli ubuthongo.

I-OX1 i-receptors nayo isandul 'ukubandakanyeka ekubaleni iziqendu zokuzintyintya ngokutya okunyanzelekileyo (i-Avena kunye ne-Bocarsly, 2012), ekwachazwa “njengekhoboka lokutya,” enye indlela yokuziphatha enyanzelekileyo eyandayo phakathi kwabantu abatyebe kakhulu (iVolkow kunye noBulumko, 2005; Pedram et al., 2013). Nangona ekuqaleni kwaboniswa ukuba ulawulo oluphambili lwe-orexin-A luvuselela indlela yokuziphatha ngokutya ngokusebenza kwiisekethe ezithile ze-hypothalamic (uFriederich et al., 2013), i-hypocretin/orexin-induced food intake ibonakala iphenjelelwa zezinye izinto ezininzi, kubandakanywa ukuthandeka kokutya, ukulingana kwamandla, inqanaba lokuvusa kunye nesimo sengqondo (Yamanaka et al., 2003; UZheng et al., 2007; Choi et al., 2010; Tsujino kunye noSakurai, 2013). Oku kuphakamisa ukuba inkqubo ye-hypocretin/orexin inokusebenzisa iipatheni zokuziphatha ezintsonkothileyo kunokonyuka kokutya kokutya (Mahler et al., 2012). Ewe, uphando lwakutsha nje lubonisa ukubandakanyeka okunokwenzeka kwe-hypocretin/orexin dysregulation ekutyeni okunyanzelekileyo kokutya okunencasa (uSmith noRobbins, 2013).

Ukutya okunyanzelekileyo kunokufunwa kwiigundane ngokutshintshana kwamaxesha okufikelela rhoqo ekutyeni kunye namaxesha okuthintelwa kokutya kwiiveki ezimbalwa, imeko ethile engapheliyo yoxinzelelo enokuvelisa iziqendu zokuzintyintya xa isixa esikhulu sokutya okunencasa sifumaneka ngokukhawuleza. Imodeli yaqinisekiswa nge-pharmacologically kwiigundane, ebonisa impembelelo yokuthintela i-topiramate kwi-intake yokutya okunyanzelekileyo (Cifani et al., 2009) efana naleyo ibonwa kubantu abazityayo (McElroy et al., 2003). Nangona idatha malunga nokubandakanyeka kwendlela ye-hypocretin / i-orexin kule nkqubo yovavanyo yokutya ngokutya yayingekho, sifunde umphumo we-GSK1059865 njengesixhobo sokuvavanya ukufaneleka kwee-receptors ze-OX1 (Piccoli et al., 2012). Okubangela umdla kukuba, i-GSK1059865, kwiidosi ze-10 kunye ne-30 mg / kg, ayikwazanga ukunqanda ukutya okunencasa kakhulu kwizilwanyana ezilawulayo (ezingavezwanga kuthintelo lokutya okujikelezayo), iqinisekisa isiphumo esincinci se-OX1 receptor blockade kumvuzo wendalo xa isenzeka. phantsi kweemeko zomzimba. Ngokuchasene noko, i-GSK1059865 ithintele ngendlela enyanzelekileyo indlela yokutya kwiimpuku ezivezwe kuxinzelelo olungapheliyo / uthintelo lokutya (Piccoli et al., 2012). Okubangel 'umdla kukuba, ukutya rhoqo kwakuthintelwe ngumchasi we-OX1 SB-334867 kwiigundane ezityekele ekutyebeni kodwa zingekho kulawulo lweempuku (White et al., 2005). Ezi ziphumo ziqinisekisile indima yosasazo lwe-OX1 ye-receptor-mediated ekuthinteleni idrive egqithisileyo eveliswa ngumnqweno ohambelana nonxunguphalo olukwajongwe kunye neziyobisi ezikhobokisayo.

Okubangel 'umdla kokutya ngokutya kwakunqatshelwe yi-DORA SB-649868, kodwa kungekhona ngumchasi okhethiweyo we-OX2 we-receptor JNJ-10397049, ebonisa ukuba iziphumo ze-SB-649868 mhlawumbi zibangelwa yi-OX1 yecandelo lesenzo sayo (Piccoli et al. , 2012). Okumangalisayo kukuba, ukungabikho kwempembelelo ye-almorexant kwizilwanyana ezivezwe kuphela kuxinzelelo olunzima lucebise ukuba inkqubo yokutshintsha amaxesha okuthintelwa kokutya ibalulekile ekubandakanyekeni kwenkqubo ye-hypocretin / orexin ekukhuthazeni ukutya okunyanzelekileyo kokutya okunencasa kakhulu (Funabashi et al., 2009; Pankevich et al., 2010). Olu qwalaselo lucebisa ukuba kule paradigm iDORA kunye ne-OX1 abachasi azisebenzi ngokuyintloko ngesiphumo sokulwa noxinzelelo. Oku akumangalisi, ngenxa yendima eyinkimbinkimbi ye-hypocretin / i-orexin ekugcinweni kokulinganisela kwamandla kunye novakalelo lwe-hypocretin / orexin neurons ukuphendula ngokuthe ngqo utshintsho lwamanqanaba e-glucose ejikelezayo kunye neempawu ze-endocrine (i-Tsujino kunye ne-Sakurai, 2013).

Ngokubanzi, iziphumo ezifunyenwe nge-GSK1059865 ziqinisekisa ukuba ukuchasana kwe-OX1 ye-receptor antagonism ayichaphazeli ngokuthe ngqo iindlela zomvuzo ezibandakanyeka ekutyeni i-hedonic, kodwa kunoko zixhasa indima ekunyanzelweni kokutya, ezo mhlawumbi zichaza uphuhliso kunye nokuzingisa kokutya okungaqhelekanga. Ukuziphatha kwabantu abatya kakhulu kwaye, kunokwenzeka, nakwizigulane ezine-bulimic. Ukongeza, ezi datha ziqaqambisa isidingo sokuphonononga kwakhona iprofayili ye-OX1 ye-receptor antagonism, ukuza kuthi ga ngoku isekelwe ikakhulu kwi-SB-334867 (Haynes et al., 2000), ikhompawundi ekukhethwe kwayo kwidosi ephezulu kunye nokuzinza kuye kwaxoxwa (Hollander et al., 2012; McElhinny et al., 2012).

Ukuza kuthi ga ngoku inani elilinganiselweyo lezifundo ze-biomarker zabantu zixhasa indima ye-hypocretin/orexin inkqubo kwi-dysregulation yokuziphatha ebonisa ukuba likhoboka, kwaye akukho namnye kubo osebenzisa i-pharmacologic agents. Utshintsho lwamanqanaba e-hypocretin/orexin egazini lwabonwa kwizinxila ngexesha lokurhoxa kotywala, lubonisa unxulumano oluhle namanqaku onxunguphalo (von der Goltz et al., 2011), ngelixa unxulumano olubi lwabonwa ngamanqaku okunqwenela abantu abangatshayiyo (von der Goltze et al., 2010). Ukubonakaliswa okwandisiweyo kwamanqanaba e-hypocretin/orexin kwafunyanwa kwigazi elisecaleni labatshayayo kunye nabaxhaphazi be-cannabis (Rotter et al., 2012). Ngelixa ukutolikwa koku kufunyenweyo kungakacaci, abantu abachatshazelwa yi-narcolepsy bafundelwa uxanduva lwabo lokulutha ngethemba lokufumana iziphumo ezinolwazi ngakumbi. Ngokufanelekileyo, i-narcolepsy iqhele ukunxulunyaniswa notshintsho kwi-hypocretin/orexin gene (Peyron et al., 1998), okubangela ukunqongophala kwe-peptide, efana naleyo ifunyenwe kwi-hypocretin/orexin KO iimpuku. Iintlukwano ezifihlakeleyo ekusebenzeni komvuzo kunye nokuziphatha kokuthatha umngcipheko kwaxelwa kwizifundo ze-narcoleptic, kodwa ukuxhaphaka kokutshaya icuba kwezi zigulana kwakungahlukanga kuluntu oluqhelekileyo (uBayard kunye noDauvilliers, 2013). Kukho iziphumo zinokubonwa ngokwahlukileyo kunye nobungqina beziphumo ezincitshisiweyo zeziyobisi kwi-hypocretin/orexin KO iimpuku (uphononongo bona uMahler et al., 2012; Boutrel et al., 2013). Okubangela umdla kukuba, izifundo ze-narcoleptic zibhengezwe zisebenzisa ukutshaya icuba kunye ne-nicotine patches njengokuzinyanga ukunciphisa ukozela kunye nokwandisa ukuvuswa (Ebben kunye neKrieger, 2012). Lilonke, iziphumo zibonisa ukuntsonkotha kubudlelwane phakathi kokuziphatha okukhobokisayo kunye nenkqubo engasebenziyo ye-hypocretin/orexin ebantwini, exhasa imfuno yezifundo ezongezelelweyo, ezigxininise ngakumbi zokuguqulela.

I-Hypocretin/orexin kunye ne-OX1 receptor kwixhala

Iincwadi zezifundo ze-physiology zichaza imimandla yangasemva kunye ne-perifornical ye-hypothalamus njengenxalenye yesekethe ye-limbic elawula "ukulwa-okanye-ukubhabha" ukuphendula kwisoyikiso esizayo (uHess no-Akert, 1955). Njengoko kukhankanyiwe ngasentla, ii-neurons ezivelisa i-hypocretin/oirexin zikwindawo yeperifornical (Peyron et al., 1998) kunye neprojekthi kuninzi lwezakhiwo zengqondo ye-limbic ezibandakanyeka kuloyiko, uxinzelelo kunye nesekethe yokuxhalaba (iShin kunye neLiberzon, 2009), ecebisa indima enokwenzeka ye-hypocretin/orexin ekulawuleni kungekuphela nje ukuphaphama kunye nokuvuka, kodwa kunye noloyiko, ixhala, kunye neempendulo zoxinzelelo (uJohnson et al., 2012a; Sears et al., 2013).

Le ngcamango yaphononongwa kule minyaka idlulileyo kwaye yashwankathelwa kumanqaku amva nje kunye nophononongo (Bisetti et al., 2006; uMathew et al., 2008; Johnson et al., 2010, 2012a). Kule minikelo abafundi abanomdla banokufumana ubungqina obuxhasa indima ye-hypocretin / i-orexin neurons ekulungiseleleni ukuzimela, ukuphefumla, ukusabela kwentliziyo kunye nokuziphatha kwi-stimuli yoxinzelelo kunye ne-panic-inducing.

I-hypothesis esebenzayo ithetha ukuba i-stimuli ecinezelayo (okanye amanqanaba aphezulu e-endogenous abalamli be-anxiogenic) inokunyusa umsebenzi kwi-hypocretin/orexin neurons, ethi yona ikhuphe i-hypocretin/orexin eninzi kwiindawo zabo zokugcina ezibekwe kwimimandla yobuchopho elawula iimvakalelo kunye nempendulo yoxinzelelo. . Emva koko i-hypocretin / i-orexin iya kutshintsha inqanaba lokuvula uloyiko, uxinzelelo kunye nesekethe yokuxhalaba ukuya kwinqanaba eliphezulu lokuvusa, elibandakanya i-vegetative, i-endocrine kunye neziganeko zokuziphatha eziqhelekileyo zokuxhalaba kunye ne-panic states. Ukuzingisa okungaqhelekanga kokukhululwa ngokugqithisileyo kwe-hypocretin/orexin kunokubonwa njengento ebalulekileyo ekugcineni ukuvuswa okuphezulu kunye nokuxhalaba, kunye noxanduva lokubuyela kwi-panic episodes kubantu abachazwe kwangaphambili, ebonisa indima ebalulekileyo ye-pathophysiological yokukhathazeka.

Idatha ebantwini ibonise ukukhutshwa okwandisiweyo kwe-extracellular hypocretin/orexin eqhutywa kukuchukunyiswa ngokweemvakalelo kwi-amygdala yezifundo ezithwaxwa sisifo sokuxhuzula sexeshana esinganyangekiyo esifakwe kwi-microdialysis probes (Blouin et al., 2013). Kolu phononongo amanqanaba e-hypocretin/orexin anyukile ngexesha lokuvuka kwaye ehla ngexesha lokulala, kodwa ezona ndawo ziphakamileyo zabonwa ngexesha lokushukumiseka okubukhali ngokweemvakalelo zombini ivalence entle kunye nengalunganga. I-amygdala ithathwa njengesiseko esisisiseko sokucubungula ubukhali kunye neemvakalelo ezimbi, ezinxulunyaniswa noxinzelelo lwe-pathologic. Kwiimpuku ukujova i-hypocretin/orexin kwi-amygdala yonyusa ixhala-njengokuziphatha (uAvolio et al., 2011). Okubangel 'umdla kukuba, amanqanaba aphezulu angaqhelekanga e-hypocretin/orexin afunyenwe kwi-cerebro-spinal fluid (CSF) yezigulane ezine-Panic Anxiety Disorders, ebonisa ukuba kunokwenzeka ukuba imeko ye-hyperactivity (uJohnson et al., 2010). Kolunye uphononongo amanqanaba aphezulu e-hypocretin / orexin alinganiswa kwigazi le-peripheral lezifundo ezine-chronic obstructive pulmonary disorder (COPD), imeko ehambelana ne-hypercapnia, i-acidosis kunye ne-10-fold-fold risk of panic attack (Zhu et al., 2011).

Iziphumo eziguquguqukayo zibonisa ukuba iimpawu ze-anxiogenic ze-hypocretin / orexin zixutyushwa ngokubandakanyeka kwe-OX1 receptors. Kwiimpuku iimpendulo ezizimeleyo kunye nokuziphatha kuxinzelelo ziye zathotyelwa lunyango lwangaphambili kunye ne-OX1 receptor antagonists, njenge-SB-334867 (Johnson et al., 2010, 2012b), GSK 1034865 (Gozzi et al., 2011) kunye ne-ACT-335827 (uSteiner et al., 2013), okanye ngeDORA, njenge-almorexant (Steiner et al., 2012). Ukuthotywa okubalulekileyo kweempendulo ezinjengokukhathazeka kwabonwa kwiiparadigms ezibandakanya uloyiko (Sears et al., 2013; Steiner et al., 2013), i-panicogenic lactate infusion (uJohnson et al., 2010), hypercapnia (Li et al., 2010; Johnson et al., 2012b), ulawulo lwe-FG-7142 (uJohnson et al., 2012a), idosi ephezulu inikotini (Plaza-Zabala et al., 2010), kunye ne-yohimbine (uRichards et al., 2008). Ubungqina bamva nje obusebenzisa iimpuku ze-OX1 kunye ne-OX2 KO zibonise indima ebalulekileyo yee-receptors ze-OX1 ezibekwe kwindawo ye-locus coeruleus ekulaleni ukufunda okunoloyiko kunye noyilo lwenkumbulo yoloyiko (Sears et al., 2013; Soya et al., 2013).

Ubungqina bokuba i-hypocretin/i-orexin-equlathe ii-neurons ifumana igalelo kwezinye ii-neuron ezivelisa i-anxiogenic peptide corticotropin releasing factor (CRF) kunye nokuba iiprojekthi ze-hypocretin/orexin neurons kwimimandla yengqondo etyebileyo kwi-CRF zicebisa ukuba ezi nkqubo zimbini ze-peptidergic zibambene ngokusebenzayo kulawulo. impendulo yoxinzelelo (Ida et al., 2000; UPañeda et al., 2005). Nangona kunjalo, ukuba le ngcamango ichanekile, iipropathi ze-anxiolytic ze-CRF-1 antagonists (iZorrilla kunye noKoob, 2004) kunye nabachasi be-OX1 baya kudlula, babonise iiprofayili ezifanayo. Okubangela umdla kukuba, uphononongo lwakutsha nje olusebenzisa i-phMRI kwiimpuku lucebisa ukuba ukubandakanyeka kwe-CRF-1 kunye ne-OX1 kwiimpendulo zoxinzelelo kunokwahlulwa ngokusebenzayo. Kolu vavanyo imephu yengqondo yokuvula i-phMRI yafunyaniswa kwiimpuku kunye ne-yohimbine kwiidosi ezaziwa ngokuvelisa iziphumo ze-anxiogenic. Unyango lwangaphambili nokuba yi-CP-154,526, umchasi okhethiweyo we-CRF-1 (uSeymour et al., 2003), okanye i-OX1 ekhethiweyo ye-receptor antagonist GSK1059865 (Gozzi et al., 2011) zenziwa. Imephu yobuchopho yokuvula i-yohimbine yathotywa yi-CP-154,526 kwimoto, i-cingulate, i-retrosplenial, i-dorsal prefrontal cortex, iinxalenye ze-dorsal ze-caudate-putamen, kunye ne-amygdala. Ngokwahlukileyo, i-GSK1059865 igxininise imephu yokuvula ye-yohimbine kwi-nucleus accumbens, i-septum, i-dorsal thalamus, i-amygdala, i-ventral hippocampus, i-orbitofrontal, i-prefrontal, i-insular, i-cingulate retrosplenial, kunye ne-piriform cortex (Gozzi e-al. 2013). Ngokubanzi, i-OX1 receptor antagonist yenza impembelelo ebanzi ngakumbi kuloyiko, uxinzelelo kunye nesekethe yokuxhalaba kunomchasi weCRF1, ethintela ukusebenza kwemimandla yenkqubo ye-dopaminergic mesolimbic. Ngokuhambelana nokuqwalaselwa kokugqibela, ukwahlukana kwafunyanwa phakathi kweziphumo ze-OX1 kunye ne-CRF-1 abachasayo kwinkqubo ye-rat mesolimbic dopamine kwi-cocaine eyenziwe ngoxinzelelo (Wang et al., 2009) kunye nokufuna inikotini (Plaza-Zabala et al., 2012).

Okubangela umdla kukuba, kwezinye izifundo zombini abachasi be-OX1 kunye nee-DORA azizange zibonise iziphumo zokuxhalaba kwiimvavanyo ezithile zokuziphatha (umzekelo, i-maze ephakanyisiweyo) (uSteiner et al., 2012; Rodgers et al., 2013). Ezi datha zihambelana nengcamango yokuba i-hypocretin / i-orexin receptor antagonists ayiguquli amanqanaba okuxhalaba kwe-basal kwiigundane, kodwa zisebenzisa iimpawu ezinjenge-anxiolytic xa amanqanaba okuxhalaba agqithiswa ngokukhawuleza ngenxa ye-stimuli enamandla njenge-acidosis / hypercapnia.

Imida kunye nesiphelo

Ingqiqo yokuqwalasela i-OX1 i-receptors njengento ekujoliswe kuyo kwiimeko ezifana ne-Anxiety Disorders, i-Drug Addiction, kunye ne-Binge Eating yahlaziywa. Ngokusekelwe kulwazi lwangoku kwindlela yokwenza, i-OX1 i-receptor antagonists kufuneka ibe neengozi ezimbalwa zophuhliso kune-DORAs. Njengoko kugxininiswe nguScammell kunye noWinrow (2011) kunye noBoutrel et al. (2013) kwi-DORAs, i-blockade engapheliyo ngexesha elifanayo zombini i-hypocretin / i-orexin receptors inokuthi: (1) ibangele iimpawu ezifana ne-narcoleptic, kuquka i-catalepsy; (2) ukuphazamisa ukwenza izigqibo ezijoliswe kwiinjongo; (3) ukunciphisa ulonwabo olunxulumene nemisebenzi enomvuzo; (4) ukubangela ukuthotywa, ukulala kunye nokuphazamiseka kokuphendula iimpendulo phantsi koxinzelelo olunzima okanye uxinzelelo; (5) impembelelo kwi-basal metabolism kunye nokwanda kobunzima bomzimba. Nangona kunjalo, ukuza kuthi ga ngoku amava omntu kunye ne-DORAs suvorexant, SB-649868 kunye ne-almorexant ayakhuthaza kakhulu, abonisa ukwenzeka okuncinci kwezi ziganeko ezimbi zikhankanywe ngasentla kwaye, ngokukodwa, akukho kufakwa kwe-narcoleptic eoisodes okanye ukuphazamiseka kokwenziwa kwezigqibo xa kuvavanywa ngaphakathi uluhlu lwethamo olucetywayo ngoku. Nangona kunjalo, idatha engaphezulu kuluntu olukhulu kunye needosi eziphezulu ziyafuneka ukufikelela kwisigqibo sokugqibela.

Okubangel 'umdla kukuba, unyango olunabachasi be-OX1 abakhethiweyo abalindelekanga ukuba babelane ngeengozi ezifanayo ze-DORA kuba kuphela i-OX2 receptor inxulunyaniswa ne-narcolepsy eboniswe kwizinja eziphethe ukuguqulwa kofuzo okuphazamisayo kule receptor (Wu et al., 2011). Iingenelo ezongezelelweyo ezinokuthi zibekho zomchasi we-OX1 ziquka: (1) Iprofayili ye-preclinical anxiolytic eyahlula kwi-benzodiazepines, i-serotonin-uptake inhibitors, kunye ne-CRF-1 antagonists; (2) Amandla okunciphisa i-hyper-arousal states ehambelana neziganeko ezixhalabisayo kunye nezinzima kunye neempawu ezifanelekileyo zomzimba, ezifana nokuhlaselwa kwe-panic okanye ukuhoxiswa kwiziyobisi eziluthayo; (3) Ukuthotywa kokuziphatha okunyanzelekileyo kunye nokuphindaphinda okuhambelana nokuziva, ukudambisa uxinzelelo, okanye ukufuna iziyobisi; (4) Ukungabikho kweziphumo kumnqweno wembuyekezo yendalo, kunye (5) nokungabikho kweziphumo ezibangela ubuthongo.

Ezi ngqwalasela zisekelwe kwidathasethi elinganiselweyo yezifundo zangaphambi kweklinikhi, ezisandul 'ukuqhutywa kunye nesizukulwana esitsha sekhompawundi ezikhethiweyo. Uphononongo olungapheliyo lwedosi alukho kwaye ke ngoko ulwazi lweengozi zexesha elide kunye nezibonelelo azikafumaneki. Ukongeza, akukho bachasi be-OX1 abakhethiweyo be-receptor baye bavavanywa ebantwini ukuza kuthi ga ngoku kwaye umqobo wokuguqulela awukacaci. Nangona kunjalo, amandla onyango athembisayo ekumodareyithweni koxinzelelo kunye nokuziphatha okunyanzelekileyo kuvuselela uphando olusisiseko kwaye ikhuthaza utyalo-mali olusebenzayo kwiinkampani ezixuba amayeza.

Ukungquzulana kwintetho yomdla

UEmilio Merlo Pich ungumsebenzi osisigxina weF. Hoffman-La Roche. Omnye umbhali uvakalisa ukuba uphando lwenziwe ngokungabikho naluphi na ubudlelwane bezorhwebo okanye bezemali obunokuthi buthathwe njengento enokubakho ukungqubana komdla.

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