Bicyclic melatonin receptor agonists containing a ring-junction nitrogen: Synthesis, biological evaluation, and molecular modeling of the putative bioactive conformation.
Employing 1,3-dipolar cycloaddition for the synthesis of the 7a-azaindole nucleus, analogues of melatonin have been synthesized and tested against human and amphibian melatonin receptors. Introducing a phenyl substituent in position 2 of the heterocyclic moiety significantly increased binding affinity to both the MT1 and MT2 receptors. Shifting the methoxy group from position 5 to 2 of the 7a-azaindole ring led to a substantial reduction of MT1 binding when MT2 recognition was maintained. We theoretically investigated the hypothesis whether the 2-methoxy function of the azamelatonin analogue 27 is able to mimic the 5-methoxy group of the neurohormone by directing its 2-methoxy function toward the methoxy binding site. DFT calculations and experimental binding differences of analogue compounds indicate that the energy gained by forming the methoxy-specific hydrogen-bond interaction should exceed the energy required for adopting an alternative conformation.
Elsner
Jan
J
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
Boeckler
Frank
F
Davidson
Kathryn
K
Sugden
David
D
Gmeiner
Peter
P
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008550:Melatonin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D009584:Nitrogen / Q000737:chemistry*; D044122:Receptor, Melatonin, MT1 / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D044123:Receptor, Melatonin, MT2 / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D013329:Structure-Activity Relationship; D014981:Xenopus
D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D008550:Melatonin; D009584:Nitrogen