STERIC ASPECTS OF ADRENERGIC DRUGS. IX. PHARMACOLOGIC AND HISTOCHEMICAL STUDIES ON ISOMERS OF COBEFRIN (-METHYLNOREPINEPHRINE)

¹ College of Pharmacy, Ohio State University, Columbus, Ohio, and Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania

Isomers of cobefrin (-methylnorepinephrine) and related agents were studied on rat vas deferens. D(-)-cobefrin and (±)-erythro-N-methylcobefrin act "directly," whereas L(+)-cobefrin, (±)-threocobefrin, (+)-desoxycobefrin, (-)-desoxycobefrin and (±)-threo-N-methylcobefrin produce very little effect on reserpine-pretreated tissues. On the normal vas deferens (+)-desoxycobefrin is more active than L(+)-cobefrin. On guinea-pig trachea, all agents except (-)-desoxycobefrin and L(+)-cobefrin are "directly" acting. Stereochemical considerations for "direct" vs. "indirect" drug effects and alpha vs. beta adrenergic effects are discussed. The catecholamine-fluorescence technique of Falck was used to demonstrate the reserpine-resistant neural uptake and retention of these isomers in the rat iris. D(-)-Cobefrin, L(+)-cobefrin and (±)-erythro-N-methylcobefrin are taken up and retained by adrenergic nerves, whereas (±)-threocobefrin and (±)-threo-N-methylcobefrin do not show these characteristics. When studied similarly, after (+)-desoxycobefrin, adrenergic nerves and their varicosities showed more fluorescence than after (-)-desoxycobefrin. This tends to support the concept that during biotransformation (-)--methyldopa is converted to (+)-desoxycobefrin, which is -hydroxylated to D(-)-cobefrin.