STRUCTURE-ACTIVITY-RELATIONSHIPS OF A SERIES OF BUSPIRONE ANALOGS AT ALPHA-1-ADRENOCEPTORS - FURTHER EVIDENCE THAT RAT AORTA ALPHA-1-ADRENOCEPTORS ARE OF THE ALPHA-1D-SUBTYPE

The activity of a series of busprione analogs at recombinant and rat t horacic aorta alpha-1 adrenoceptors was investigated. Compound affinit y for recombinant alpha-1A, alpha-1B and alpha-1D adrenoceptors from h uman and animal sources was determined by radioligand binding assays u sing membranes prepared from rat-1 fibroblasts expressing recombinant receptors with ]iodo-4-hydroxyphenyl)-ethyl-aminomethyl-tetralone as t he radioligand. Compound affinity and functional activity at rat aorti c alpha-1 adrenoceptors were determined using endothelium denuded ring s contracted with phenylephrine. BMY 7378 iperazinyl]-ethyl)-8-azaspir o[4.5]decane-7,9-dione dihydrochloride} and MDL 73005EF lmethylamino)e thyl]8-azaspiro[4,5]decane-7,9-dione hydrochloride} were found to have significant selectivity for the alpha-1D-subtype and were high affini ty antagonists of the alpha-1 adrenoceptors in the rat aorta, Leverage plot analysis of affinities of the buspirone analogs and a series of structurally diverse alpha-1 antagonists for recombinant alpha-1 adren oceptors and rat aorta alpha-1 adrenoceptors demonstrate that the alph a-1 adrenoceptors in the rat aorta are predominantly of the alpha-1D s ubtype.