8-NH₂-Boldine, an Antagonist of α_1Aand α_1BAdrenoceptors without Affinity for the α_1DSubtype: 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 alpha (1A), alpha (1B) and alpha (1D) adrenoceptors (AR) using membranes prepared from rat-1 fibroblasts stably expressing each alpha (1)-AR subtype. All the compounds tested competed for [ (125)I]-HEAT binding with steep and monophasic curves. The most interesting compound was 8-NH (2)-boldine, which retains the selective affinity for alpha(1A)-AR (pKi = 6.37 +/- 0.21) vs. alpha(1B)-AR (pKi = 5.53 +/- 0.11) exhibited by 1,2,9,10-tetraoxygenated aporphines, but shows low affinity for alpha(1D)-AR (pKi < 2.5). Binding studies on native adrenoceptors present in rat cerebral cortex confirms the results obtained for human cloned alpha (1)-AR subtypes. The compounds selective for the alpha (1A) subtype discriminate two binding sites in rat cerebral cortex confirming a mixed population of alpha (1A)- and alpha (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 alpha (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 alpha(1A)-AR in this vessel. On the contrary, a poor correlation seems to exist between the affinity of 8-NH (2)-boldine for cloned alpha (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 alpha (1)-AR mediates the adrenergic response in this vessel.

In vitro functional evaluation of isolaureline, dicentrine and glaucine enantiomers at 5‐HT2 and α1 receptors

“…This pattern of behaviour has also been observed in studies carried out in our laboratory on the individual enantiomers of roemerine ( 2a ) and nuciferine ( 3a ) . Similarly, both enantiomers of these three compounds, as well as apomorphine ( 4a ) and N ‐n‐propylnorapomorphine ( 4b ), have been found to antagonize α 1 receptors . We therefore decided to investigate whether the structurally related compounds, isolaureline ( 2b ), dicentrine ( 2c ) and glaucine ( 3b ) follow the same pattern.…”

New aporphinoid 5-HT2A and α1A antagonists via structural manipulations of nantenine

“…26 Others have documented the affinity trends of aporphines at the α 1A receptor, but no study has done so with nantenine as the lead. 12 One prior study has investigated the structure-affinity relationships of nantenine at α 1 receptors. 27 Here it was reported that replacement of the C1 methoxy group with a hydroxyl group gave improved α 1 affinity.…”

Evaluation of structural effects on 5-HT2A receptor antagonism by aporphines: Identification of a new aporphine with 5-HT2A antagonist activity

“…1–8 As central nervous system (CNS) receptor ligands, aporphines have been found to possess high affinity for a number of dopamine receptors (predominantly D 1 and D 2 ), 9–12 serotonin (5-HT) receptors 13–15 and α-adrenergic receptors. 6,16 Furthermore, aporphines are known with both agonist and antagonist activity at neuroreceptor sites. The continued exploration of the aporphine template over the last few decades has been driven to some extent by the opportunity/promise for discovery of new ligands with high potency and selectivity for subtypes of the above-mentioned receptors.…”