Potent antinociceptive effects of TRK-820, a novel κ-opioid receptor agonist

Endoh, Takashi; Matsuura, Hirotoshi; Tajima, Atsushi; Izumimoto, Naoki; Tajima, Chiko; Suzuki, Tomohiko; Saitoh, Akiyoshi; Suzuki, Tsutomu; Narita, Minoru; Tseng, Leon F.; Nagase, Hiroshi

doi:10.1016/s0024-3205(99)00417-8

Cited by 94 publications

(90 citation statements)

References 15 publications

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“…Relatively few synthetic compounds have been developed that have a high selectivity for KOP receptors. Until recently, the most specific of these compounds were U69,593, U50,488 and their congeners spiradoline and enadoline, which have limited efficacy following oral administration Endoh et al 1999). In a recent report, Prisinzano and Rothman (2008) suggested that analogs of the chemicals isolated from S. divinorum may prove to be excellent research tools and give greater insight into opioid receptor-mediated phenomena.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats

et al. 2009

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Background and rationale Research interests regarding the psychopharmacology of salvinorin A have been motivated by the recreational use and widespread media focus on the hallucinogenic plant, Salvia divinorum. Additionally, kappa opioid (KOP) receptor ligands may have therapeutic potential in the treatment of some neuropsychiatric conditions, including drug dependence and mood disorders. Salvinorin A is a selective KOP agonist, but only a few studies have explored the discriminative stimulus effects of this compound. Objective This study compared the discriminative stimulus effects of salvinorin A and two synthetic derivatives of salvinorin B to the KOP agonists, U69,593 and U50,488. Materials and methods Sixteen male Sprague-Dawley rats trained to discriminate U69,593 (0.13 mg/kg, s.c., N=8) or U50,488 (3.0 mg/kg, i.p., N=8) under a fixed-ratio 20 schedule of food reinforcement were administered substitution tests with salvinorin A (0.125-3.0 mg/kg, i.p.). The animals trained to discriminate U69,593 were also administered substitution tests with salvinorin B ethoxymethyl ether (0.005-0.10 mg/kg, i.p.) and salvinorin B methoxymethyl ether (0.03-0.10 mg/kg, i.p.). Another eight rats were trained to discriminate 2.0 mg/kg salvinorin A and tested with U69,593 (0.04-0.32 mg/kg) and U50,488 (0.4-3.2 mg/kg). Results Salvinorin A and both synthetic derivatives of salvinorin B substituted completely for U69,593. Additionally, cross-generalization was observed between salvinorin A and both KOP agonists.Conclusion These findings support previous reports indicating that the discriminative stimulus effects of salvinorin A are mediated by kappa receptors. Future studies may assist in the development and screening of salvinorin A analogs for potential pharmacotherapy.

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Section: Discussionmentioning

confidence: 99%

Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats

et al. 2009

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“…Therefore, although it seems unlikely that a putative anti-inflammatory action underlies the presently reported antinociceptive action of Pz 2 and Pz 3, further specific studies about the anti-inflammatory potential of these compounds are necessary to clarify this point. Opioid agonists are known to cause antinociception in thermal stimulation tests (23)(24)(25)(26), a fact that suggests an opioid-like action for the tested pyrazole derivatives. As will be discussed below, the present suggestion of the involvement of opioid mechanisms in Pz 3-induced antinociception was corroborated by the finding that naloxone prevented Pz 3-induced antinociception.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive effect of novel pyrazolines in mice

Tabarelli

Rubin

Berlese

et al. 2004

Braz J Med Biol Res

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The antinociceptive effect of six novel synthetic pyrazolines (3-ethoxymethyl-5-ethoxycarbonyl-1H-pyrazole (Pz 1) and its corresponding 1-substituted methyl (Pz 2) and phenyl (Pz 3) analogues, and 3-(1-ethoxyethyl)-5-ethoxycarbonyl-1H-pyrazole (Pz 4) and its corresponding 1-substituted methyl (Pz 5) and phenyl (Pz 6) analogues) was evaluated by the tail immersion test in adult male albino mice. The animals (N = 11-12 in each group) received vehicle (5% Tween 80, 10 ml/kg, sc) or 1.5 mmol/kg of each of the pyrazolines (Pz 1-Pz 6), sc. Fifteen, thirty and sixty minutes after drug administration, the mice were subjected to the tail immersion test. Thirty minutes after drug administration Pz 2 and Pz 3 increased tail withdrawal latency (vehicle = 3.4 ± 0.2; Pz 2 = 5.2 ± 0.4; Pz 3 = 5.9 ± 0.4 s; mean ± SEM), whereas the other pyrazolines did not present antinociceptive activity. Doseeffect curves (0.15 to 1.5 mmol/kg) were constructed for the bioactive pyrazolines. Pz 2 (1.5 mmol/kg, sc) impaired motor coordination in the rotarod and increased immobility in the open-field test. Pz 3 did not alter rotarod performance and spontaneous locomotion, but increased immobility in the open field at the dose of 1.5 mmol/kg. The involvement of opioid mechanisms in the pyrazoline-induced antinociception was investigated by pretreating the animals with naloxone (2.75 µmol/kg, sc). Naloxone prevented Pz 3-but not Pz 2-induced antinociception. Moreover, naloxone pretreatment did not alter Pz 3-induced immobility. We conclude that Pz 3-induced antinociception involves opioid mechanisms but this is not the case for Pz 2.

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“…Â óñëîâèÿõ TRK-820-îïîñðåäîâàííîé ñóïðàñïèíàëüíîé àíàëüãåçèè îòíîøå-íèå ïîêàçàòåëåé ÝÄ 50 ñåäàöèè/ÝÄ 50 àíòèíîöèöåïöèè îêàçàëîñü ñóùåñòâåííî âûøå ïî ñðàâíåíèþ ñ òàêîâû-ìè äëÿ U-50,488 è ICI-199,441 [104]. Êðîìå òîãî, íàë-ôóðàôèí íå âûçûâàë ïñèõîòîìèìåòè÷åñêèõ ýôôåêòîâ ó çäîðîâûõ äîáðîâîëüöåâ [101,105], à òàêaeå ýôôåêòîâ ïîäêðåïëåíèÿ èëè àâåðñèâíûõ ðàññòðîéñòâ â äîçàõ äî 80 ìêã/êã [42].…”

Section: -(1-áåíçîôóðàí-4-èë)-n-ìåòèë-n-[(5r7s8s)-7-ïèððîëèäèí-1-èunclassified

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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Potent antinociceptive effects of TRK-820, a novel κ-opioid receptor agonist

Cited by 94 publications

References 15 publications

Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats

Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats

Antinociceptive effect of novel pyrazolines in mice

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

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