Kappa-opioid ligands in the study and treatment of mood disorders

Abstract

The biological basis of mood is not understood. Most research on mood and affective states has focused on the roles of brain systems containing monoamines (e.g., dopamine, norepinephrine, serotonin). However, it is becoming clear that endogenous opioid systems in the brain may also be involved in regulation of mood. In this review, we focus on the potential utility of kappa-opioid receptor (KOR) ligands in the study and treatment of psychiatric disorders. Research from our group and others suggests that KOR antagonists might be useful for depression, KOR agonists might be useful for mania, and KOR partial agonists might be useful for mood stabilization. Currently available agents have some unfavorable properties that might be addressed through medicinal chemistry. The development of KOR-selective agents with improved drug-like characteristics would facilitate preclinical and clinical studies designed to evaluate the possibility that KORs are a feasible target for new medications.

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

“…Studies correlating the dysphoric effects of κOR agonists to the G-protein-independent activation of the p38 MAPK pathway (8,13,15) suggest that identification of κOR agonists biased to G-protein-mediated signaling could lead to the development of therapeutics with reduced side effects. This suggestion has spurred the search for novel κOR ligands or scaffolds that could provide novel treatment strategies for a variety of disorders where κOR involvement has been implicated (16,17).…”

“…Previously identified synthetic κOR ligands were mostly nitrogenous compounds with a tertiary amine group (16). However, about a decade ago, Salvinorin A (Sal A), a nonnitrogenous diterpene extracted from the Mexican mint Salvia divinorum and characterized by the presence of a furyl-δ-lactone motif ( Fig.…”

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

“…Îïèîèäíûå k-ðåöåïòîðû âîâëå÷åíû â ìíîãî÷èñëåí-íûå ôèçèîëîãè÷åñêèå ïðîöåññû, âêëþ÷àÿ àíàëüãåçèþ, ðåãóëÿöèþ íåéðîýíäîêðèííîé ñåêðåöèè, âîäíîãî áà-ëàíñà, ïèòüåâîãî è ïèùåâîãî ïîâåäåíèÿ, âåãåòàòèâíûõ ôóíêöèé, ìåõàíèçìîâ îáó÷åíèÿ, ïàìÿòè [12].…”

“…Îïèîèäíûå k-ðåöåïòîðû ïðåäñòàâëåíû êàê â ÖÍÑ [5,12], òàê è íà ïåðèôåðèè [13,14], è ñïåöèôè÷åñêè àêòèâèðóþòñÿ ýíäîãåííûìè ëèãàíäàìè, îáðàçóþùè-ìèñÿ èç ïðîäèíîðôèíà [15]. Âûñîêèé óðîâåíü k-ðå-öåïòîðîâ ýêñïðåññèðóåòñÿ â âåãåòàòèâíûõ öåíòðàõ ãî-ëîâíîãî, ñïèííîãî ìîçãà, ñòðóêòóðàõ, îòâåòñòâåííûõ çà âîñïðèÿòèå íîöèöåïòèâíîé èíôîðìàöèè [16 -18], êîãíèòèâíûå ôóíêöèè, ýìîöèîíàëüíîå ïîâåäåíèå, ñîç-íàíèå [1,2], à òàêaeå íà ïåðèôåðèè â ãàíãëèÿõ òðîé-íè÷íîãî íåðâà, çàäíèõ êîðåøêîâ ñïèííîãî ìîçãà, êëå-òî÷íûõ òåëàõ òîíêèõ ìèåëèíèçèðîâàííûõ è íåìèåëè-íèçèðîâàííûõ íîöèöåïòèâíûõ àôôåðåíòíûõ îêîí÷àíèé [19 -21], òåðìèíàëÿõ ñåíñîðíûõ íåéðîíîâ êîaeè, ìûøö, ñóñòàâàõ, âíóòðåííèõ îðãàíàõ, ëèìôîöè-òàõ, ëåéêîöèòàõ, êàðäèîìèîöèòàõ [22 -25].…”

“… ëèòåðàòóðå èìåþòñÿ ñâåäåíèÿ îá àíòèàääèêòèâ-íîì, àíòèíîöèöåïòèâíîì, äèóðåòè÷åñêîì, àíòèïñèõî-òè÷åñêîì, ïðîòèâîñóäîðîaeíîì, àíêñèîëèòè÷åñêîì, íåéðîïðîòåêòîðíîì, àíòèäåïðåññèâíîì, ïðîòèâîâîñ-ïàëèòåëüíîì, êàðäèîïðîòåêòîðíîì ýôôåêòàõ ëèãàíäîâ îïèîèäíûõ k-ðåöåïòîðîâ [12,17,26]. Àêòèâàöèÿ k-ðå-öåïòîðîâ ñåëåêòèâíûìè àãîíèñòàìè ìîäóëèðóåò èì-ìóííûé ñòàòóñ, ïîäàâëÿåò ýêñïðåññèþ ÂÈ×-1 [27].…”