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.
Rivara
Silvia
S
Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G. P. Usberti 27/A, Campus Universitario, 43100 Parma, Italy.
Lodola
Alessio
A
Mor
Marco
M
Bedini
Annalida
A
Spadoni
Gilberto
G
Lucini
Valeria
V
Pannacci
Marilou
M
Fraschini
Franco
F
Scaglione
Francesco
F
Sanchez
Rafael Ochoa
RO
Gobbi
Gabriella
G
Tarzia
Giorgio
G
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