Studies on the structure-activity relationships of adrenergic .BETA.-mimetic benzylamine derivatives. V. 9-Aryl-1H-2,3,7,8,9,10-hexahydrobenzo[d,e]quinolines.

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The synthesis and adrenergic β-mimetic activities of stereoisomeric 9-aryl-5, 6-dihydroxy-1 H-2, 3, 7, 8, 9, 10-hexahydrobenzo [d, e] quinolines (5), which should be regarded as constrained analogs of the benzylamine (2), the tetrahydronaphthalenes (3) and trimetoquinol (TMQ, 1), are presented. Structure-activity relationships of these compounds were explained in terms of various spatial orientations of the functional groups in these molecules suggested by inspection of Dreiding model. The conformations of 3b-trans and 5b-trans, both of which are potent tracheal relaxants, are the type A orientation of the functional groups where the catechol and trimethoxyphenyl groups are approximately anti to each other. 5b-cis which can not hold the type A orientation was only 1/130 as active as 5b-trans. The spatial orientation of the functional groups in TMQ in the crystalline state was found to be the type A. These results may suggest that the conformation of TMQ required for manifesting its β2-stimulating activity in the biophase is probably similar to that in the crystalline state. Contrary to the previous finding that 2 and 3b-trans were active in both β2 and β1 adrenoceptors, 5b-trans was found to possess high selectivity for β2-adrenoceptors.

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