In vitro and in vivo pharmacological profile of the 5-benzyl analogue of 14-methoxymetopon, a novel mu opioid analgesic with reduced propensity to alter motor function

Opioids are the most effective analgesics for pain management, and efficient pain control is a therapeutic priority. Herein, we describe the synthesis and pharmacological activities of the 5-benzyl analogue of the mu opioid analgesic 14-methoxymetopon (14-MM). The result of the replacement of the 5-methyl in 14-MM with a benzyl group on in vitro opioid receptor binding and functional profiles, and in vivo behavioural properties, i.e. nociception and motor activity, was investigated. In rodent brain membranes, the 5-benzyl derivative showed high affinity at the micro opioid receptor and decreased interaction with delta and kappa receptors, hence displaying a similar binding profile as 14-MM. It displayed potent agonist activity in vitro and in vivo. In in vitro guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTPgammaS) binding assay, it activated G-proteins in rat brain membranes through a micro opioid receptor-mediated mechanism having significantly enhanced potency compared to DAMGO (D-Ala(2),Me-Phe(4),Gly-ol(5)]enkephalin), and to the micro opioid agonist morphinans 14-MM, 14-O-methyloxymorphone (14-OMO) and morphine. In vivo, the 5-benzyl analogue of 14-MM elicited dose-dependent and naloxone-sensitive antinociceptive effects in hot-plate and tail-flick tests in mice after subcutaneous (s.c.) administration. Its analgesic potency was comparable to 14-MM, and was 50-fold higher than that of morphine. Contrary to morphine, 14-MM and 14-OMO, no motor dysfunction was produced by the new opioid in the mouse rotarod test at any of the tested doses. In summary, the 5-benzyl analogue of 14-MM emerged as a novel potent mu opioid antinociceptive agent with reduced propensity to cause unwanted motor impairment.