Synthesis and nicotinic binding studies on enantiopure pinnamine variants with an 8-azabicyclo[3.2.1]octane moiety.
Bioisosteric replacement of the 9-azabicyclo[4.2.1]nonane pharmacophoric element of the novel alkaloidal marine toxine pinnamine (5) by the 8-azabicyclo[3.2.1]octane moiety resulted in conformationally restricted analogues 6a and 6c of (-)-ferruginine (4). Key step in the diastereoselective synthesis of these pyranotropanes was the condensation of enantiopure ecgonine methyl ester (9) from the "chiral pool" with the lithium anion of N-tert-butylbutyraldimin and subsequent cyclisation with TFA. The potential nAChR ligands were tested for their in vitro affinity for the (alpha4)2(beta2)3 and the alpha7* nAChR subtypes. Despite obvious structural similarities with the potent alkaloids pinnamine (5) and (-)-ferruginine (4) the pyranotropanes 6a and 6c exhibited distinctly lower nAChR affinities.
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Institut für Pharmazeutische Chemie der Philipps-Universität Marburg, Germany.
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D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D034242:Cyclooctanes / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C483143:8-azabicyclo(3.2.1)octane; D001372:Aza Compounds; D034242:Cyclooctanes; D007202:Indicators and Reagents; D011978:Receptors, Nicotinic