Pharmacological characterization of the novel selective kappa opioid receptor agonists 10-Iodo-Akuammicine and 10-Bromo-akuammicine in mice.

Akuammicine (AKC), an indole alkaloid, is a kappa opioid receptor (KOR) full agonist with a moderate affinity. 10-Iodo-akuammicine (I-AKC) and 10-Bromo-akuammicine (Br-AKC) showed higher affinities for the KOR with K(i) values of 2.4 and 5.1 nM, respectively, and high selectivity for the KOR over other opioid receptors. Both were KOR full agonists. As AKC and derivatives have distinctly different chemical structures from other KOR agonists, herein we investigated whether Br-AKC and I-AKC produced similar pharmacological effects as typical KOR agonists. Br-AKC and I-AKC inhibited compound 48/80-induced scratching in a dose-dependent manner, with ED(50) values of 3.0 and 1.3 mg/kg (s.c.), respectively, indicating anti-pruritic activities. Side effects of I-AKC and Br-AKC and their promotion of KOR phosphorylation and internalization were examined using doses in the effective anti-scratch dose range, at 1.9-3.8x ED(50) and 1.7-3.3x ED(50), respectively. At 5 mg/kg, Br-AKC and I-AKC produced profound conditioned place aversion (CPA). Br-AKC (10 mg/kg), but not I-AKC (5 mg/kg), reduced novelty-induced hyperlocomotion, and Br-AKC impaired rotarod performance more profoundly than I-AKC. Br-AKC, but not I-AKC, caused KOR phosphorylation at S369 in the mouse brain and KOR internalization in the ventral tegmental area. These results indicate that Br-AKC and I-AKC produce anti-scratch effect and CPA, similar to typical KOR agonists. However, there are some differences between the two. In addition, KOR phosphorylation and internalization in mouse brains are not associated with CPA but may be related to hypolocomotion and impaired rotarod performance. This is the first in vivo pharmacological characterization of AKC derivatives.