Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans

Walsh, Sharon; Strain, Eric C.; Abreu, Mariza Toledo de; Bigelow, George E.

doi:10.1007/s002130100788

Cited by 232 publications

(173 citation statements)

References 24 publications

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“…In the past, studies on the precise role of KORs in humans were hampered by the lack of selective agonists, although studies with compounds such as cyclazocine and ketocyclazocine suggested that KOR agonists were psychotomimetic (28). More recently, human studies with the highly selective KOR agonist enadoline (42) indicated that KOR activation induced visual distortions, feelings of unreality, and depersonalization. These effects of enadoline are reminiscent of those previously reported for Salvinorin A (2, 3).…”

Section: Discussionmentioning

confidence: 99%

Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

Roth

Baner

Westkaemper

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

736

739

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Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited 3 H-bremazocine binding to cloned opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent opioid agonist at cloned opioid receptors expressed in human embryonic kidney-293 cells and at native opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT 2A serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for opioid receptors, opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that opioid receptors play a prominent role in the modulation of human perception.

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Section: Discussionmentioning

confidence: 99%

Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

Roth

Baner

Westkaemper

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

736

739

View full text Add to dashboard Cite

show abstract

“…) to both the selective kappa agonist, enadoline (20, 40 80 & 160 μg/70 kg, i.m. ), and to the full mu agonist, hydromorphone (Walsh et al 2001b). In this case, the profile of subjective effects for butorphanol overlapped considerably with hydromorphone (e.g., increased ratings of good effects, liking, nodding, etc.…”

mentioning

confidence: 85%

“…We were initially interested in butorphanol because of its potential kappa activity and the recognized potential of kappa agents for use in the treatment of cocaine dependence (see (Walsh et al 2001b). However, there are numerous unwanted side effects after administration of selective kappa agonists, including diuresis, sweating, sedation, dizziness, visual distortions, feelings of depersonalization, dysphoria, and, at higher doses, psychotomimetic effects (Dershwitz et al 1991;Kumor et al 1986;Walsh et al 2001b).…”

mentioning

confidence: 99%

“…However, there are numerous unwanted side effects after administration of selective kappa agonists, including diuresis, sweating, sedation, dizziness, visual distortions, feelings of depersonalization, dysphoria, and, at higher doses, psychotomimetic effects (Dershwitz et al 1991;Kumor et al 1986;Walsh et al 2001b). This host of undesirable effects would likely limit their utility as pharmacotherapies, and indeed limited our ability to test higher doses of the full kappa agonist, enadoline, due to problematic dysphoric and hallucinogeniclike effects (Walsh et al 2001b). We identified butorphanol as a potential agent of interest speculating that its combined partial kappa agonist and partial mu agonist effects could make it more readily tolerated and reinforcing, respectively, thus enhancing its therapeutic acceptability.…”

mentioning

confidence: 99%

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Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade

et al. 2007

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Rationale-Butorphanol exerts activity at mu, kappa and delta opiate receptors in rats and monkeys but produces predominant mu-like effects in humans.Objectives-To determine if the kappa receptor-mediated actions of butorphanol could be unmasked or enhanced by giving it in combination with naltrexone, an opioid antagonist with higher affinity for mu versus kappa receptors.Methods-Ten healthy adult inpatient volunteers (8 M, 2 F), with opioid abuse histories, completed this double-blind, randomized, placebo-controlled study. Naltrexone (0, 1, 3, 10 or 30 mg, p.o.) was administered 1 hr before butorphanol (0, 6 or 12 mg/70 kg, i.m.) during 15 test sessions. An array of physiological (e.g., vital signs, urine output, subject-and observer-rated measures was collected before and for 4 hr after drug administration.Results-Naltrexone alone produced no direct effects. Butorphanol alone produced typical mu-, but not kappa-, related physiological effects (e.g., miosis, respiratory depression) and produced mood and drug effects considered typical of both mu (e.g., "liking," "good drug effects") and kappa agonists (e.g., increases in perceptual disturbances). Naltrexone pretreatment led to significant butorphanolinduced diuresis (i.e., increased urine output and decreased urine osmolality). Naltrexone generally produced a dose-dependent blockade of these subjective responses.Conclusion-These data suggest that naltrexone antagonism unveiled the kappaergic activity of butorphanol as measured by diuresis, while subjective responses generally attributed to mu versus kappa receptors were not dissociable. Moreover, these data demonstrate that butorphanol exerts physiologically relevant kappa agonist activity at these supraanalgesic doses in humans.

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“…Èõ ôàðìàêîëîãè÷åñêèé ïðîôèëü áûë ñõîäåí ñ òàêî-âûì òèïè÷íûõ àãîíèñòîâ k-ðåöåïòîðîâ, îïèñàííûõ âûøå, ÷òî òàêaeå ïîäòâåðäèëîñü â õîäå êëèíè÷åñêèõ èññëåäîâàíèé [69]. Ýíàäîëèí è PD117302 ïåðâîíà-÷àëüíî ðàçðàáàòûâàëèñü êàê âûñîêîýôôåêòèâíûå àíàëüãåòèêè [70 -72], íåéðîïðîòåêòîðû è àíòèêîí-âóëüñàíòû [73,74].…”

Section: òðàíñ-2-(34-äèõëîðôåíèë)-n-ìåòèë-n-unclassified

Опиоидные Κ-Рецепторы Как Молекулярная Мишень Для Создания Нового Поколения Обезболивающих Лекарственных Средств

Гречко¹,

Спасов²,

Штарёва³

2016

Хим.-фарм. ж.

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ÎÏÈÎÈÄÍÛÅ k-ÐÅÖÅÏÒÎÐÛ ÊÀÊ ÌÎËÅÊÓËßÐÍÀß ÌÈØÅÍÜ ÄËß ÑÎÇÄÀÍÈß ÍÎÂÎÃÎ ÏÎÊÎËÅÍÈß ÎÁÅÇÁÎËÈÂÀÞÙÈÕ ËÅÊÀÐÑÒÂÅÍÍÛÕ ÑÐÅÄÑÒÂ 1 Âîëãîãðàäñêèé ãîñóäàðñòâåííûé ìåäèöèíñêèé óíèâåðñèòåò, Ðîññèÿ, Âîëãîãðàä 2 Âîëãîãðàäñêèé ìåäèöèíñêèé íàó÷íûé öåíòð, Ðîññèÿ, 400131, Âîëãîãðàä, ïë. Ïàâøèõ Áîðöîâ, 1 Â îáçîðå êðàòêî îïèñàíû îñíîâíûå îñîáåííîñòè ñòðîåíèÿ è ôóíêöèé êàïïà-îïèîèäíîãî ðåöåïòîðà, ïðèâåäåíà õàðàêòåðèñòèêà åãî àãîíèñòîâ è ïåðñïåêòèâà èõ èñïîëüçîâàíèÿ â ìåäèöèíå. Èç âñåõ ïîäòèïîâ îïèîèäíûõ ðåöåïòîðîâ èìåííî k-ðåöåïòîðû ÿâëÿþòñÿ íàè-áîëåå ïðèâëåêàòåëüíûìè äëÿ ñîçäàíèÿ íîâûõ ïðåïàðàòîâ ñ ìèíèìàëüíûì êîëè÷åñòâîì íåaeåëàòåëüíûõ ýôôåêòîâ. Îïèîèäíûé k-ðåöåïòîð -ïðåäñòàâèòåëü ñóïåðñåìåéñòâà ìå-òàáîòðîïíûõ G-áåëîê ñîïðÿaeåííûõ ðåöåïòîðîâ. Îïèîèäíûå k-ðåöåïòîðû øèðîêî ïðåä-ñòàâëåíû êàê â ÖÍÑ, òàê è íà ïåðèôåðèè. Îíè âîâëå÷åíû â ìíîãî÷èñëåííûå ôèçèîëîãè-÷åñêèå ïðîöåññû, âêëþ÷àÿ àíàëüãåçèþ, ðåãóëÿöèþ íåéðîýíäîêðèííîé ñåêðåöèè, âîäíîãî áàëàíñà, ïèòüåâîãî è ïèùåâîãî ïîâåäåíèÿ, âåãåòàòèâíûõ ôóíêöèé, ìåõàíèçìîâ îáó÷å-íèÿ, ïàìÿòè. Íà ñåãîäíÿøíèé äåíü èìååòñÿ èíôîðìàöèÿ î ñóùåñòâîâàíèè 3 ïîäòèïîâ k-îïèîèäíûõ ðåöåïòîðîâ, íî èçó÷åííîé ÿâëÿåòñÿ ëèøü ìîëåêóëÿðíàÿ õàðàêòåðèñòèêà ïåðâîãî ïîäòèïà (k 1 ).Êëþ÷åâûå ñëîâà: îïèîèäíàÿ ñèñòåìà; îïèîèäíûé k-ðåöåïòîð; àãîíèñòû îïèîèäíîãî k-ðåöåïòîðà.Îïèîèäíàÿ ðåöåïòîðíàÿ ñèñòåìà ñîñòîèò èç 4 òèïîâ ãåòåðîãåííûõ G-áåëîê-ñîïðÿaeåííûõ (GPCR) m-, d-, k-è ORL 1 (îïèîèäîïîäîáíûõ) ðåöåïòîðîâ, êîòîðûå ôàð-ìàêîëîãè÷åñêè îõàðàêòåðèçîâàíû, êëîíèðîâàíû, ðàç-ëè÷àþòñÿ ïåðâè÷íîé ñòðóêòóðîé, àíàòîìè÷åñêèì ðàñ-ïðåäåëåíèåì, ïðîôèëåì ôàðìàêîëîãè÷åñêîé àêòèâíî-ñòè, ôèçèîëîãè÷åñêèìè ôóíêöèÿìè [1 -3]. Ñòðîåíèå îïèîèäíîãî k-ðåöåïòîðàÁåëîê k-ðåöåïòîðà ïðèíàäëåaeèò ê À êëàññó ñóïåð-ñåìåéñòâà ìåòàáîòðîïíûõ GPCR [4,5], ñîñòîèò èç 380 àìèíîêèñëîòíûõ îñòàòêîâ, 7 ãèäðîôîáíûõ Ü-ñïèðà-ëåé, èíòåãðèðîâàííûõ â êëåòî÷íóþ ìåìáðàíó, à òàêaeå N-ãëèêîçèëèðîâàííîãî è Ñ-ïàëüìèòèðîâàííîãî êîíöå-âûõ ôðàãìåíòîâ (ðèñ. 1) [6].Ïîëàãàþò, ÷òî âòîðàÿ è òðåòüÿ âíåêëåòî÷íûå ïåòëè, à òàêaeå âåðõóøêà ÒÌ-4 ÿâëÿþòñÿ êëþ÷åâûìè ôðàã-ìåíòàìè äëÿ âûñîêîñåëåêòèâíîãî ñâÿçûâàíèÿ ðåöåï-òîðà ñ ëèãàíäàìè [7]. Èçó÷åíèå õèìåðíûõ ñòðóêòóð ïîêàçàëî, ÷òî ïåòëÿ EL-2 íåîáõîäèìà äëÿ ïðîÿâëåíèÿ àêòèâíîñòè äèíîðôèíà [8]. Êàïïà-áåëîê ñîäåðaeèò îñ-òàòîê Glu 297 íà òðåòüåé âíåêëåòî÷íîé ïåòëå, êîòîðûé ÿâëÿåòñÿ åãî "àäðåñíûì" ôðàãìåíòîì äëÿ âûñîêîàô-ôèííîãî ñâÿçûâàíèÿ ñ norBNI (íîðáèíàëòîðôèìèí). Âíóòðèêëåòî÷íàÿ ÷àñòü ðåöåïòîðà ñîäåðaeèò 2 îñòàòêà òèðîçèíà Tyr 87 è Tyr 157 , ÿâëÿþùèõñÿ ìèøåíÿìè äëÿ ôîñôîðèëèðîâàíèÿ òèðîçèíêèíàçîé. Ôîñôîðèëèðîâà-íèå ýòèõ îñòàòêîâ ìîaeåò îêàçûâàòü ðàçëè÷íûå ýôôåê-òû íà ÃÒÔ-çàâèñèìîå ñâÿçûâàíèå G-áåëêîâ ñ äðóãèìè êëåòî÷íûìè áåëêàìè, òàêèìè êàê b-àððåñòèí èëè RGS áåëêàìè (ðåãóëÿòîð G-áåëîê ñèãíàëèçàöèè) è ìîäóëè-ðîâàòü àêòèâíîñòü îïèîèäíûõ k-ðåöåïòîðîâ [9, 10]. Äðóãèì âàaeíûì ó÷àñòêîì ôîñôîðèëèðîâàíèÿ ÿâëÿåò-ñÿ îñòàòîê ñåðèíà Ser 369 íà C-òåðìèíàëè [11]. Ðàñïðåäåëåíèå è ôóíêöèè îïèîèäíûõ k-ðåöåïòîðîâÎïèîèäíûå k-ðåöåïòîðû ïðåäñòàâëåíû êàê â ÖÍÑ [5,12], òàê è íà ïåðèôåðèè [13,14], è ñïåöèôè÷åñêè àêòèâèðóþòñÿ ýíäîãåííûìè ëèãàíäàìè, îáðàçóþùè-ìèñÿ èç ïðîäèíîðôèíà [...

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Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans

Abstract: These results are discussed with respect to the potential use and safety of kappa agonists for clinical indications.

Cited by 232 publications

References 24 publications

Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade

Опиоидные Κ-Рецепторы Как Молекулярная Мишень Для Создания Нового Поколения Обезболивающих Лекарственных Средств

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