title: MT1-selective melatonin receptor ligands: synthesis, pharmacological evaluation, and molecular dynamics investigation of N-{[(3-O-substituted)anilino]alkyl}amides.
abstract: The design of compounds selective for the MT1 melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT1 subtype, and only few selective compounds have been reported so far. N-(Anilinoalkyl)amides are a versatile class of melatonin receptor ligands that include nonselective MT1/MT2 agonists and MT2-selective antagonists. We synthesized a new series of N-(anilinoalkyl)amides bearing 3-arylalkyloxy or 3-alkyloxy substituents at the aniline ring, looking for new potent and MT1-selective ligands. To evaluate the effect of substituent size and shape on binding affinity and intrinsic activity, both flexible and conformationally constrained derivatives were prepared. The phenylbutyloxy substituent gave the best result, providing the partial agonist 4 a, which was endowed with high MT1 binding affinity (pKi=8.93) and 78-fold selectivity for the MT1 receptor. To investigate the molecular basis for agonist recognition, and to explain the role of the 3-arylalkyloxy substituent, we built a homology model of the MT1 receptor based on the β2 adrenergic receptor crystal structure in its activated state. A binding mode for MT1 agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT1 selectivity of compounds with lipophilic arylalkyloxy substituents.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, V.le G. P. Usberti 27A, 43124 Parma (Italy).
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Valeria
authors.initials: V
authors.lastname: Lucini
authors.forename: Silvana
authors.initials: S
authors.lastname: Dugnani
authors.forename: Francesco
authors.initials: F
authors.lastname: Scaglione
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.forename: Simone
authors.initials: S
authors.lastname: Lucarini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000814:Aniline Compounds / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D044122:Receptor, Melatonin, MT1 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000814:Aniline Compounds; D008024:Ligands; D044122:Receptor, Melatonin, MT1