Tricyclic alkylamides as melatonin receptor ligands with antagonist or inverse agonist activity.
This work reports the design and synthesis of novel alkylamides, characterized by a dibenzo[a,d]cycloheptene nucleus, as melatonin (MLT) receptor ligands. The tricyclic scaffold was chosen on the basis of previous quantitative structure-activity studies on MT1 and MT2 antagonists, relating selective MT2 antagonism to the presence of an aromatic substituent out of the plane of the MLT indole ring. Some dibenzo seven-membered structures were thus selected because of the noncoplanar arrangement of their benzene rings, and an alkylamide chain was introduced to fit the requirements for MLT receptor binding, namely, dibenzocycloheptenes with an acylaminoalkyl side chain at position 10 and dibenzoazepines with this side chain originating from the nitrogen atom bridging the two phenyl rings. Binding affinity at human cloned MT1 and MT2 receptors was measured by 2-[125I]iodomelatonin displacement assay and intrinsic activity by the GTPgammaS test. The majority of the compounds were characterized by higher affinity at the MT2 than at the MT1 receptor and by very low intrinsic activity values, thus confirming the importance of the noncoplanar arrangement of the two aromatic rings for selective MT2 antagonism. Dibenzocycloheptenes generally displayed higher MT1 and MT 2affinity than dibenzoazepines. N-(8-Methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylmethyl)propionamide (4c) and -butyramide (4d) were the most selective MT2 receptor antagonists of the series, with MT2 receptor affinity comparable to that of melatonin and as such among the highest reported in the literature for MLT receptor antagonists. The acetamide derivative 4b produced a noticeable reduction of GTPgammaS binding at MT2 receptor, thus being among the few inverse agonists described.
Dipartimento di Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, I-20129 Milano, Italy.
Valeria
V
Lucini
Marilou
M
Pannacci
Francesco
F
Scaglione
Franco
F
Fraschini
Sivia
S
Rivara
Marco
M
Mor
Fabrizio
F
Bordi
Pier Vincenzo
PV
Plazzi
Gilberto
G
Spadoni
Annalida
A
Bedini
Giovanni
G
Piersanti
Giuseppe
G
Diamantini
Giorgio
G
Tarzia
D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D003986:Dibenzocycloheptenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D053284:Polyunsaturated Alkamides; D011869:Radioligand Assay; D051381:Rats; D044122:Receptor, Melatonin, MT1 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D044123:Receptor, Melatonin, MT2 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D003986:Dibenzocycloheptenes; D008024:Ligands; C488789:N-(8-methoxy-10,11-dihydro-5H-dibenzo(a,d)cycloheptene-10-ylmethyl)butyramide; C488788:N-(8-methoxy-10,11-dihydro-5H-dibenzo(a,d)cycloheptene-10-ylmethyl)propionamide; D053284:Polyunsaturated Alkamides; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D016244:Guanosine 5'-O-(3-Thiotriphosphate)