THE CATECHOLAMINE Alpha--RECEPTOR AS A POLYANIONIC CYSTEINE PROTEIN.SELECTIVE COVALENT OCCUPANCY BY POLYAMINEDISULFIDES

Polyaminedisulfides represent a novel class of irreversible (non-equilibrium) antagonists of thealpha-adrenoreceptor. The following developments are presented: a) discovery of two distinct series oftetraminedisulfides each incorporating a unique member displaying optimum activity surpassingthat of a previous prototype by two orders of magnitude; b) unprecedented selectivity for thea-receptor as illustrated by lack of activity against the 5-hydroxytryptamine, the histamine andnicotinic receptors - however, some variable effects at high concentrations on some muscar.inicreceptors; c) unusual mechanism of o-receptor saturation suggestive of cooperative interactions; d)elucidation of the role of structural symmetry and dÌstribution on alpha-blocking activity anddeduction of topographical model for the active sites; e) discovery of a differentìal blockade ofNA- and A-elicited responses; f) possible role of multiple anionic sites in calcium binding; g)potentiating effect of certain tetramines on NA- and A-induced contractions; h) preliminaryconclusions on the molecular selectivity of the best prototype antagonist (BHC) made radioactivewith tritium.