Cyclazocine revisited

Abstract

Recently synthesized compounds which have long-term mu antagonist activity and short-term kappa agonist effects prevent self-administration of cocaine and morphine in rats. Cyclazocine, a compound synthesized in 1962 and studied in animals and man in the 1960's and in the early 1970's is a mu antagonist in rats and man and is a potent kappa agonist in both species. It also prevents self-administration of cocaine and morphine in rats. Although it produces unpleasant side effects in man, subjects become tolerant to these side effects but not to the antagonistic actions of the drug after prolonged administration.

Effects of the Mixed Mu/Kappa Opioid Nalbuphine on Cocaine-Induced Changes in Subjective and Cardiovascular Responses in Men

“…In preclinical studies, kappa opioids attenuated many of the abuse-related and locomotor-activating effects of cocaine, and these findings suggested that kappa opioids might be useful for the clinical treatment of cocaine abuse (Archer et al, 1996; see for a review Mello and Negus, 2000). Cocaine self-administration studies in non-human primates indicated that kappa opioids with mu receptor activity reduced cocaine selfadministration more effectively, and with fewer adverse side effects, than kappa selective opioids Bowen et al, 2003).…”

“…Kappa opioid agonists are one candidate medication for cocaine abuse treatment (Archer et al, 1996;Mello and Negus, 2000). Accumulating evidence from in vivo and in vitro studies shows that pharmacological modulation of kappa opioid receptors can affect the activity of dopaminergic neurons that are involved in mediating the neurochemical and behavioral effects of cocaine .…”

“…Archer and co-workers first postulated that kappa and mu opioid combinations might be useful for treatment of cocaine abuse, because both kappa agonists and mu antagonists reduce dopamine release from the nucleus accumbens (Archer et al, 1996). In support of this hypothesis, compounds with mixed activity at kappa and mu opioid receptors (eg ethylketocyclazocine (EKC), Mr2033) decreased cocaine self-administration by rhesus monkeys more consistently, and with fewer side effects than selective kappa opioid agonists (Negus et al, 1997;Negus, 1998b, 2000).…”

Effects of Mixed-Action κ/μ Opioids on Cocaine Self-Administration and Cocaine Discrimination by Rhesus Monkeys

“…An alternative approach to modulation of cocaine's dopaminergic effects is to administer k-opioid receptor agonists (Archer et al, 1996). k Agonists attenuate a number of neurobiological effects of cocaine in rats, such as cocaineinduced increases in extracellular dopamine levels in the nucleus accumbens (Maisonneuve et al, 1994) and immediate-early gene expression in the striatum (Crawford et al, 1995;Steiner and Gerfen, 1995).…”

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

“… îòëè÷èå îò ïîñëåäíåãî îíè íå âûçûâàëè ðåñïèðàòîðíîé äåïðåññèè, ôèçè÷åñêîé è ïñèõè÷åñêîé çàâèñèìîñòè. Áîëåå òîãî, èìåëèñü âñå îñíîâàíèÿ äëÿ ñåðüåçíîãî ðàññìîòðåíèÿ öèêëàçîöèíà è áðåìàçîöèíà â êà÷åñòâå ïîòåíöèàëüíûõ ëåêàðñòâåííûõ ñðåäñòâ äëÿ ëå÷åíèÿ àëêîãîëüíîé è íàðêîòè÷åñêîé çàâèñèìîñòè [41,42]. Îäíàêî èç-çà ðàçâèòèÿ ïñèõîòîìèìåòè÷åñêèõ ýôôåêòîâ, âêëþ÷àþùèõ íàðóøåíèÿ âîñïðèÿòèÿ ïðî-ñòðàíñòâà è âðåìåíè, ñõåìû òåëà, çðèòåëüíûå ãàëëþ-öèíàöèè, äåïåðñîíàëèçàöèþ è ïîòåðþ ñàìîêîíòðîëÿ, äàëüíåéøåå èçó÷åíèå ýòèõ âåùåñòâ áûëî ïðèîñòàíîâ-ëåíî [39].…”