PHARMACOLOGY OF N-SUBSTITUTED AZIDOMORPHINES

Abstract

N-allylnorazidomorphine (NAM), N-allyl-14-hydroxynorazidomorphine (NOAM), N-cyclopropylmethylnorazidomorphine (CAM) and N-cyclopropylmethyl-14-hydroxynorazidomorphine (COAM) were synthetized and their pharmacological effect in comparison to naloxone and naltrexone were analyzed. While naloxone and naltrexone are pure antagonists at all points, the N-substituted norazidomorphines were found to be more potent antagonists than naloxone in some of the tests and extremely potent pure agonists in others. Using CAM for routine work we differentiated between opiate A-receptors which are stimulated and opiate B-receptors which are antagonized by CAM. Opiate A-receptors were found to be involved in the behavioral disturbances (inhibition of conditioned avoidance responses, characteristic EEG changes, elimination of slow wave and paradoxical sleep, etc.) caused by the opiates. The guinea-pig ileum and mouse vas deferens are the suitable isolated organs for testing A-receptors. Opiate B-receptors are responsible for the analgesic, antitussive, cataleptic, respiratory depressant and hypotensive effects of the opiates. The isolated nictitating membrane of the cat is an appropriate model for testing the B-receptors. The hypothesis is proposed that A-receptors relate to cholinergic and B-receptors to adrenergic mechanisms; the N-substituted norazidomorphines are tools for the analysis of the two kinds of opiate receptors.