8-NH₂-Boldine, an Antagonist of α_1A and α_1B Adrenoceptors without Affinity for the α_1D Subtype: Structural Requirements for Aporphines at α₁-Adrenoceptor Subtypes

Abstract

Structure-activity analysis of 21 aporphine derivatives was performed by examining their affinities for cloned human α_1A, α_1B and α_1D adrenoceptors (AR) using membranes prepared from rat-1 fibroblasts stably expressing each α₁-AR subtype. All the compounds tested competed for [¹²⁵ I]-HEAT binding with steep and monophasic curves. The most interesting compound was 8-NH₂-boldine, which retains the selective affinity for α _1A-AR (pKi = 6.37 ± 0.21) vs. α _1B-AR (pKi = 5.53 ± 0.11) exhibited by 1,2,9,10-tetraoxygenated aporphines, but shows low affinity for α _1D-AR (pKi < 2.5). Binding studies on native adrenoceptors present in rat cerebral cortex confirms the results obtained for human cloned α₁-AR subtypes. The compounds selective for the α_1A subtype discriminate two binding sites in rat cerebral cortex confirming a mixed population of α_1A- and α_1B-AR in this tissue. All compounds are more selective as inhibitors of [³ H]-prazosin binding than of [³ H]-diltiazem binding to rat cerebral cortical membranes. A close relationship was found between affinities obtained for cloned α_1A-AR and inhibitory potencies on noradrenaline-induced contraction or inositol phosphate accumulation in tail artery, confirming that there is a homogeneous functional population of α _1A-AR in this vessel. On the contrary, a poor correlation seems to exist between the affinity of 8-NH₂-boldine for cloned α_1D-AR and its potency as an inhibitor of noradrenaline-induced contraction or inositol phosphate accumulation in rat aorta, which confirms that a heterogeneous population of α₁-AR mediates the adrenergic response in this vessel.

Abbreviations

NA:noradrenaline

α₁-AR:α₁-adrenoceptor

MDO:methylenedioxy

Aporphines - human cloned α₁-adrenoceptor subtypes - cerebral cortex - aorta - tail artery - cyclic nucleotide phosphodiesterases

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