Structure-activity studies with ring E analogues of methyllycaconitine. Synthesis and evaluation of enantiopure isomers of selective antagonist at the alpha3 nicotinic receptor.
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 alpha3 and alpha7 receptors as racemic compound 3. This indicates that the binding at nicotine acetylcholine receptors (nAchRs) is probably non-stereospecific.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt. kadiga99@yahoo.com
K A
KA
Ismail
S C
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Bergmeier
D000157:Aconitine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002038:Bungarotoxins / Q000378:metabolism; D002855:Chromatography, Thin Layer; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008566:Membranes / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000157:Aconitine; D002038:Bungarotoxins; D007202:Indicators and Reagents; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C054634:methyllycaconitine