MOLECULAR PROPERTIES OF THE ADRENERGIC a-RECEPTORIII - Origin of topographicol duqlism in the reaction of a receptor thiolwith symmetrical and unsymmetrical polyamine disulfides.

structure actiuity relationship studies previously led tothe discovery of two distinct classes of tetramine-disulfides (l) and (II)each exhibiting optimum adrenergic alpha-blocking activity. The more potentone (l) was shown to uniquely discriminate between noradrenaline (NA)and adrenaline (A) binding sites. The unusual receptor topographical dualismtoward (l) and (ll) led to an investigation of the role of striclural symmetry in their interaction vvith the receptor. To this end, a series ol unsymmetricaldisulfide analogs (x-z) where half of (l) was retained and the otherhalf was made of unsubstituted N-(tr-aminoalkyl)cysteamines (I'l) and its homologs were synthesized and evaluated as alpha blockers. In addition the role ol the number of basic nitrogens on activity was also examined. It was found that the presence of four nitrogens is necessary for optimum activity. Moreover, it was diiscovered that optimum alpha-blockingpotency is obtained when the respective halves of the two best prototypes (I) and (II) ol symmetrical structures are fused compound (XVI) . Thisnew unsymmetrical tetramine disulftde has a potency approaching that of (l) and its receptor saturation mechanism is similar. Moreover, it also shares with (l) the ability to discriminate between NA and A eliciteil responses.The effect of methylation of a single inner nitrogen on potency allowed theconclusion that each hall of the unsymmetrical disulfide (XVI) respectively occupy hall of the sites for (l) and half of those for (ll). Accordingly, thepreviously observed topographical dualism toward (l) and (11) can best beaccommoclated by a model where two clistinct sets ol sites crossing eachother over the same receptor thiol are involved. The possible significance ofthe anionic site multiplicity of the alpha-receptor is briefly discussed.