Analgesic activity and opioid receptor selectivity of stereoisomers of ohmefentanyl isothiocyanate

Ohmefentanyl is a very potent and highly selective agonist for mu -opioid r eceptors. We now study analgesia, in vitro activity and opioid receptor aff inity of the stereoisomers of ohmefentanyl isothiocyanate. We found that so me isomers of ohmefentanyl. isothiocyanate had a potent analgesic effect an d that all isomers except (3R,4S,2'S)-ohmefentanyl isothiocyanate had a mor e potent inhibitory action on the electrically evoked contractions of mouse vas deferens than of guinea pig ileum. The inhibitory actions could be ant agonized by naloxone. However, compared with the activity of the correspond ing stereoisomers of ohmefentanyl, these ohmefentanyl isothiocyanates had s ignificantly reduced analgesia and in vitro activity. They also inhibited t he binding of [H-3]DPDPE ([D-Pen(2),D-Pen(5)]enkephalin) and [H-3]DAGO ([D- Ala(2),Mephe(4),Gly-ol(5)]enkephalin) to opioid receptors in mouse brain me mbranes. The inhibitory effect of stereoisomers of ohmefentanyl isothiocyan ate at mu -opioid receptors was markedly lower than that of their parent co mpounds. The affinity of stereoisomers of ohmefentanyl isothiocyanate, for delta -opioid receptors was, however, greater than or equal to that of thei r corresponding stereoisomers of ohmefentanyl. The results showed that the introduction of an isothiocyanato group into the phenyl ring in position-1 of ohmefentanyl reduced bioactivity and affinity to mu -opioid receptors bu t that the selectivity of these compounds for delta -opioid receptors was e nhanced. Isomer (3R,4S,2'R)-ohmefentanyl isothiocyanate showed highest sele ctivity for delta -opioid receptors (K-i(mu)/K-i(delta) = 13.6) and potent analgesic activity (ED50 = 0.25 mg/kg). (C) 2001 Elsevier Science BY. All r ights reserved.