title: Molecular properties of the adrenergic alpha-receptor. III - Origin of topographical dualism in the reaction of a receptor thiol with symmetrical and unsymmetrical polyamine disulfides.
abstract: Structure activity relationship studies previously led to the discovery of two distinct classes of tetramine-disulfides [(I) and (II)] each exhibiting optimum adrenergic alpha-blocking activity. The more potent one (I) was shown to uniquely discriminate between noradrenaline (NA) and adrenaline (A) binding sites. The unusual receptor topographical dualism toward (I) and (II) led to an investigation of the role of structural symmetry in their interaction with the receptor. To this end, a series of unsymmetrical disulfide analogs (x-z) where half of (I) was retained and the other half was made of unsubstituted N-(omega-aminoalkyl)cysteamines [as present in (II) and its homologs] were synthesized and evaluated as alpha-blockers. In addition, the role of 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 discovered that optimum alpha-blocking potency is obtained when the respective halves of the two best prototypes (I) and (II) of symmetrical structures are fused [compound (XVI)]. This new unsymmetrical tetramine disulfide has a potency approaching that of (I) and its receptor saturation mechanism is similar. Moreover, it also shares with (I) the ability to discriminate between NA and A elicited responses. The effect of methylation of a single inner nitrogen on potency allowed the conclusion that each half of the unsymmetrical disulfide (XVI) respectively occupy half of the sites for (I) and half of those for (II). Accordingly, the previously observed topographical dualism toward (I) and (II) can best be accommodated by a model where two distinct sets of sites crossing each other over the same receptor thiol are involved. The possible significance of the anionic site multiplicity of the alpha-receptor is briefly discussed.
mesh_terms: D000317:Adrenergic alpha-Antagonists; D000818:Animals; D003543:Cysteamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004220:Disulfides / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011073:Polyamines / Q000378:metabolism* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011941:Receptors, Adrenergic / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D000317:Adrenergic alpha-Antagonists; D004220:Disulfides; D011073:Polyamines; D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; D013438:Sulfhydryl Compounds; D003543:Cysteamine