A potent new class of .kappa.-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines

Abstract

The synthesis of 4-substituted 1-(arylacetyl)-2-[(alkylamino)methyl]piperazines (10-22, 26, 27, and 30-33) and their activities as kappa-opioid receptor agonists are described. This includes a range of 4-acyl and 4-carboalkoxy derivatives with the latter series showing the greatest kappa-agonist activity. In particular, methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate (18) displays exceptional potency and selectivity. It showed the following activities in functional in vitro assays: rabbit vas deferens (kappa-specific tissue) IC50 = 0.041 nM, rat vas deferens (mu-specific tissue) IC50 > 10,000 nM, and hamster vas deferens (delta-specific tissue) IC50 > 10,000 nM. Compound 18 is also a highly potent antinociceptive agent, as determined in the mouse acetylcholine-induced abdominal constriction test: ED50 = 0.000 52 mg/kg, sc. The activity of 18 resides solely in its 3(R)-enantiomer. The kappa-agonist activity in both the 4-acyl and the 4-carbamate series is sensitive to the size of the 4-substituent. In addition, it would appear that an appreciable negative electrostatic potential in this region of the molecule is an important requirement for optimal potency.

Recent advances in selective opioid receptor agonists and antagonists

“…The first example of these compounds is U50488 (84) that has 50-fold selectivity for k receptor over m receptor. 159 Other agonists belonging to this class are U69593 (85), 160 PD117302 (86), 161,162 CI977 (enadoline (87)), 163,164 GR-89696 (88), [165][166][167] piperidine analogues (89) of GR-89696, 168,169 and pyrrolidinyl ethylacetamide derivatives (90,91), 170 all of which show high affinity and selectivity for k receptor over m and d receptors. A morphinan derivative, TRK-820 (92), exhibits high potency and k selectivity over m and d receptors.…”

Recent development and potential use of µ‐ and κ‐opioid receptor ligands in positron emission tomography studies

“…The uptake of the active (R) isomer, also known as [ 11 C]GR103545, correlated with the known distribution of k-OR. On the other hand, the inactive (S-) enantiomer, (1)-GR89696, showed a homogeneous brain uptake (IC 50 , R 5 0.018 nM; S 5 6 nM [Naylor et al, 1993;Ravert et al, 2002]). …”

“…4-substituted 1-(arylacetyl)-2-[(alkylamino)-methyl]piperazines identified methyl 4-[ (3,4-dichlorophenyl)acetyll-3-[(l-pyrrolidinyl)methyl]-l-piperazinecarboxylate (GR89696) as a highly potent and selective k-OR agonist [Hayes et al, 1990;Birch et al, 1991;Naylor et al, 1993]. Ravert et al [1999] reported the radiolabeling of racemic [ 11 C]GR89696.…”

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

“…[88] áûë ñèíòåçèðîâàí îäèí èç íàèáîëåå ñèëüíîäåéñòâóþùèõ è âûñîêîñåëåêòèâíûõ àãîíèñòîâ îïèîèäíûõ k 2 -ðåöåïòîðîâ GR89,696 (ðèñ. 8), ïðîÿâ-ëÿâøèé ñâîéñòâà àíàëüãåòèêà â äîçå 0,00052 -0,0012 ìã/êã [30].…”