Highly Potent and Selective MT2 Melatonin Receptor Full Agonists from Conformational Analysis of 1-Benzyl-2-acylaminomethyl-tetrahydroquinolines.
Molecular superposition models guided the design of novel melatonin receptor ligands characterized by a 2-acylaminomethyltetrahydroquinoline scaffold. Starting from the structure of N-anilinoethylamide ligands, the flexible chain was conformationally constrained to reproduce the bioactive conformation of melatonin. Structure-activity relationships were investigated, focusing on the substituent at the nitrogen atom, the position of the methoxy group, and the replacement of the amide side chain by urea and thiourea groups. The compounds were tested for binding affinity and intrinsic activity at human MT1 and MT2 receptors. Structural optimization resulted in N-[(1-benzyl-1,2,3,4-tetrahydro-5-methoxyquinolin-2-yl)methyl]propionamide (UCM1014), with picomolar MT2 binding affinity (K(i) = 0.001 nM), more than 10000-fold selectivity over the MT1 receptor, and a full agonist profile (GTPγS test), being the most potent MT2-selective full agonist reported to date. Molecular dynamics simulations provided a rationale for high binding affinity, stereoselectivity, and agonist behavior of these novel melatonin receptor ligands based on superposition models and conformational preference.
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo" , Piazza Rinascimento 6, I-61029 Urbino, Italy.
Gilberto
G
Spadoni
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo" , Piazza Rinascimento 6, I-61029 Urbino, Italy.
Annalida
A
Bedini
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo" , Piazza Rinascimento 6, I-61029 Urbino, Italy.
Simone
S
Lucarini
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo" , Piazza Rinascimento 6, I-61029 Urbino, Italy.
Michele
M
Mari
Institut de Recherches Servier , 125 Chemin de Ronde, F-78290 Croissy sur Seine, France.
Daniel-Henri
DH
Caignard
Institut de Recherches Servier , 125 Chemin de Ronde, F-78290 Croissy sur Seine, France.
Jean A
JA
Boutin
Institut de Recherches Servier , 125 Chemin de Ronde, F-78290 Croissy sur Seine, France.
Philippe
P
Delagrange
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano , Via Vanvitelli 32, I-20129 Milano, Italy.
Valeria
V
Lucini
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano , Via Vanvitelli 32, I-20129 Milano, Italy.
Francesco
F
Scaglione
Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124 Parma, Italy.
Alessio
A
Lodola
Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124 Parma, Italy.
Franca
F
Zanardi
Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124 Parma, Italy.
Daniele
D
Pala
Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124 Parma, Italy.
Marco
M
Mor
Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124 Parma, Italy.
Silvia
S
Rivara
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D056004:Molecular Dynamics Simulation; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D011804:Quinolines; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; C000603802:UCM1014