title: Toward the definition of stereochemical requirements for MT2-selective antagonists and partial agonists by studying 4-phenyl-2-propionamidotetralin derivatives.
abstract: New derivatives of 4-phenyl-2-propionamidotetralin (4-P-PDOT) were prepared and tested on cloned MT1 and MT2 receptors, with the purpose of merging previously reported pharmacophores for nonselective agonists and for MT2-selective antagonists. A 8-methoxy group increases binding affinity of both (±)-cis- and (±)-trans-4-P-PDOT, and it can be bioisosterically replaced by a bromine. Conformational analysis of 8-methoxy-4-P-PDOT by molecular dynamics, supported by NMR data, revealed an energetically favored conformation for the (2S,4S)-cis isomer and a less favorable conformation for the (2R,4S)-trans one, fulfilling the requirements of a pharmacophore model for nonselective melatonin receptor agonists. A new superposition model, including features characteristic of MT2-selective antagonists, suggests that MT1/MT2 agonists and MT2 antagonists can share the same arrangement for their pharmacophoric elements. The model correctly predicted the eutomers of (±)-cis- and (±)-trans-4-P-PDOT. The model was validated by preparing three dihydronaphthalene derivatives, either able or not able to reproduce the putative active conformation of 4-P-PDOT.
authors: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino Carlo Bo, Piazza Rinascimento 6, I-61029 Urbino, Italy.
authors: Annalida
authors: A
authors: Bedini
authors: Simone
authors: S
authors: Lucarini
authors: Gilberto
authors: G
authors: Spadoni
authors: Giorgio
authors: G
authors: Tarzia
authors: Francesco
authors: F
authors: Scaglione
authors: Silvana
authors: S
authors: Dugnani
authors: Marilou
authors: M
authors: Pannacci
authors: Valeria
authors: V
authors: Lucini
authors: Caterina
authors: C
authors: Carmi
authors: Daniele
authors: D
authors: Pala
authors: Silvia
authors: S
authors: Rivara
authors: Marco
authors: M
authors: Mor
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D054333:Drug Partial Agonism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D041681:NIH 3T3 Cells; D011869:Radioligand Assay; D051381:Rats; D044122:Receptor, Melatonin, MT1 / Q000819:agonists / Q000037:antagonists & inhibitors; D044123:Receptor, Melatonin, MT2 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: C114459:4-phenyl-2-propionamidotetraline; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D013764:Tetrahydronaphthalenes