Structure-activity studies with ring E analogues of methyllycaconitine. Synthesis and evaluation of enantiopure isomers of selective antagonist at the α3 nicotinic receptor

Abstract The four diastereomers 4a – d of methyllycaconitine (MLA) analogue 3 (R=(CH 2 ) 3 Ph, R′=CH 3 ) have been synthesized in enantiomerically pure form by coupling both ( S )- and ( R )-2-(methylsuccinimido)benzoic acid ( 5a and 5b ) with both ( S )- and ( R )-3-hydroxymethyl- N -(3-phenyl) propylpiperidine ( 6a and 6b ) using TBTU. These compounds were assayed for potency as nicotinic acetylcholine receptor (nAChRs) antagonist. All the four diastereomers showed the same potency at both the α3 and α7 receptors as racemic compound 3 . This indicates that the binding at nicotine acetylcholine receptors (nAchRs) is probably non-stereospecific.