STRUCTURE AFFINITY RELATIONSHIPS OF 12-SULFONYL DERIVATIVES OF 5,8,8A,9,10,11,12,12A,13,13A-DECAHYDRO-6H-ISOQUINO[2,1-G][1,6]NAPHTHYRIDINES AT ALPHA-ADRENOCEPTORS

Analogues of the potent alpha-2-adrenoceptor antagonist (8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13, 13a-decahydro-3-methoxy-12-(methylsulfonyl)-6H-isoquino[2,1-g] [1,6]naphthyridine (1b) were prepared and evaluated for alpha-1- and alpha-2-adrenoceptor affinity. Affinity for alpha-2-adrenoceptors was assessed by displacement of [H-3]yohimbine from rat cerebral cortical membranes and although 1b and close structural analogues demonstrated high affinity, none were selective for the alpha-2A or alpha-2B subtypes reputedly present in this tissue. All of the high affinity alpha-2-adrenoceptor ligands were, however, selective with respect to [H-3]prazosin (alpha-1) binding. Affinity for [H-3]yohimbine-labeled alpha-2-adrenoceptors was found to be highly dependent on the stereochemistry of the tetracyclic system. The 8a-beta, 12a-alpha, 13a-alpha diastereomer of 1 (56) had moderate affinity for alpha-2-adrenoceptors while the 8a-beta, 12a-beta, 13a-alpha diastereomer (55) had very low affinity. The affinity and selectivity of these agents for alpha-2-adrenoceptors was found to correspond to that observed for several isomeric yohimbine analogues which have similar relative and absolute stereochemistries. Deviation from the structure of 1 by opening the B ring, changing the position of the sulfonamide nitrogen, or changing the attachment of the D ring led to a dramatic decrease in alpha-2-adrenoceptor affinity. High binding affinity was found to correlate with functional antagonism in the guinea pig ileum. The reversal of clonidine-induced mydriasis in the rat was used to assess bioavailability and indicated that 1b was a potent alpha-2-adrenoceptor antagonist in vivo.