N-(substituted-anilinoethyl)amides: design, synthesis, and pharmacological characterization of a new class of melatonin receptor ligands.
A novel series of melatonin receptor ligands, characterized by a N-(substituted-anilinoethyl)amido scaffold, along with preliminary structure-activity relationships (SARs), is presented. MT1 and MT2 receptor binding affinity and intrinsic activity have been modulated by the introduction of different substituents on the aniline nitrogen, on the benzene ring, and on the amide side chain. Modulation of intrinsic activity and MT2 selectivity of the newly synthesized compounds has been achieved by applying SAR models previously developed, providing compounds with different binding and intrinsic activity profiles. Compound 3d, with a bulky ss-naphthyl group, behaves as an MT2-selective antagonist with sub-nM affinity. Size reduction of the substituent enhances intrinsic activity, as in the nonselective N-methyl-anilino agonist 3i. The phenyl derivative 3g is an MT2-selective partial agonist, with MT2 binding affinity higher than melatonin, showing promising sleep-promoting and antianxiety properties in animal models.
Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G. P. Usberti 27/A, Campus Universitario, 43100 Parma, Italy.
Silvia
S
Rivara
Alessio
A
Lodola
Marco
M
Mor
Annalida
A
Bedini
Gilberto
G
Spadoni
Valeria
V
Lucini
Marilou
M
Pannacci
Franco
F
Fraschini
Francesco
F
Scaglione
Rafael Ochoa
RO
Sanchez
Gabriella
G
Gobbi
Giorgio
G
Tarzia
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D015195:Drug Design; D054333:Drug Partial Agonism; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D000814:Aniline Compounds; D014151:Anti-Anxiety Agents; D008024:Ligands; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2