Received for publication October 2, 2007.
Revised December 15, 2007.
Accepted for publication December 17, 2007.

2-Methoxymethyl-salvinorin B is a Potent Kappa Opioid Receptor Agonist with Longer-Lasting Action in vivo Than Salvinorin A

Abstract

Salvinorin A (Sal A) is a naturally occurring, selective opioid receptor (KOPR) agonist with a short duration of action in vivo. Pharmacological properties of a C(2) derivative, 2-methoxymethyl-salvinorin B (MOM-Sal B), were characterized. MOM-Sal B bound to KOPR with high selectivity and displayed ~3 fold higher affinity than U50,488H and Sal A. It acted as a full agonist at KOPR in [³⁵S]GTPS binding and was ~5 and ~7 fold more potent than U50,488H and Sal A, respectively. In CHO cells stably expressing KOPR, all three agonists internalized or down-regulated KOPR to similar extents, with MOM-Sal B being the most potent. In mice, MOM-Sal B (0.05-1 mg/kg, s.c.) caused immediate and dose-dependent immobility lasting ~3 hr which was blocked by norbinaltorphimine. In contrast, ambulation in a Y-maze was increased when rats received MOM-Sal B (1-5 mg/kg, s.c.). Additionally, MOM-Sal B (0.5-5 mg/kg, i.p.) produced antinociception (hot plate test) and hypothermia in a dose-dependent manner in rats. MOM-Sal B was more potent than U50,488H in both tests and more efficacious than U50,488H in the hot plate test. These latter two in vivo effects were blocked by norbinaltorphimine, indicating KOPR-mediated actions. Sal A at 10 mg/kg elicited neither antinociception nor hypothermia 30 min after administration to rats. In summary, MOM-Sal B is a potent and efficacious KOPR agonist with longer-lasting in vivo effects than Sal A.

Key words: Kappa opioid receptor, Salvia divinorum, Salvinorin A, down-regulation, hot plate, internalization