Design and synthesis of N-(3,3-diphenylpropenyl)alkanamides as a novel class of high-affinity MT2-selective melatonin receptor ligands.
A novel series of melatonin receptor ligands was discovered by opening the cyclic scaffolds of known classes of high affinity melatonin receptor antagonists, while retaining the pharmacophore elements postulated by previously described 3D-QSAR and receptor models. Compounds belonging to the classes of 2,3- and [3,3-diphenylprop(en)yl]alkanamides and of o- or [(m-benzyl)phenyl]ethyl-alkanamides were synthesized and tested on MT(1) and MT(2) receptors. The class of 3,3-diphenyl-propenyl-alkanamides was the most interesting one, with compounds having MT(2) receptor affinity similar to that of MLT, remarkable MT(2) selectivity, and partial agonist or antagonist behavior. In particular, the (E)-m-methoxy cyclobutanecarboxamido derivative 18f and the di-(m-methoxy) acetamido one, 18g, have sub-nM affinity for the MT(2) subtype, with more than 100-fold selectivity over MT(1), 18f being an antagonist and 18g a partial agonist on GTPgammaS test. Docking of 18g into a previously developed MT(2) receptor model showed a binding scheme consistent with that of other antagonists. The MT(2) expected binding affinities of the new compounds were calculated by a previously developed 3D-QSAR CoMFA model, giving satisfactory predictions.
Bedini
Annalida
A
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino Carlo Bo, Piazza Rinascimento 6, 61029 Urbino, Italy.
Spadoni
Gilberto
G
Gatti
Giuseppe
G
Lucarini
Simone
S
Tarzia
Giorgio
G
Rivara
Silvia
S
Lorenzi
Simone
S
Lodola
Alessio
A
Mor
Marco
M
Lucini
Valeria
V
Pannacci
Marilou
M
Scaglione
Francesco
F
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D044123:Receptor, Melatonin, MT2 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism
D000081:Acetamides; D000475:Alkenes; D000577:Amides; D001555:Benzene Derivatives; D001597:Benzylidene Compounds; D003503:Cyclobutanes; D008024:Ligands; C517233:N-(3,3-bis(3-methoxyphenyl)-2-propenyl)acetamide; C517234:N-(3-(3-methoxyphenyl)-3-phenyl-2-propenyl)cyclobutanecarboxamide; D044123:Receptor, Melatonin, MT2; D016244:Guanosine 5'-O-(3-Thiotriphosphate)