Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as new conformationally restricted ligands for melatonin receptors.
J Med Chem
; 39(16): 3089-95, 1996 Aug 02.
Article
en En
| MEDLINE
| ID: mdl-8759629
Tetrahydroanthracene, tetrahydrophenanthrene, and tetrahydrophenalene moieties were used to design novel constrained melatoninergic agents. Compounds 1 and 2 were synthesized from the cyclization of the aryl succinic acids 6a,b followed by catalytic reduction, Curtius degradation to the amino derivatives, and acetylation. The phenalene derivatives 3 were prepared by cyclization of the aza lactones of the corresponding alpha-N-acetyl amino acids. The ketone derivatives were reduced directly by catalytic hydrogenation to produce the compounds 3. The different compounds were evaluated in vitro in binding assays using 2-[125I] iodomelatonin and chicken brain membranes. Melatonin and 2-acetamido-8-methoxytetralin were used as the reference compounds. The results showed the superiority of the dihydrophenalene framework 3 over those of tetrahydroanthracene and tetrahydrophenanthrene. 3a had relatively good affinity for melatonin receptors (Ki = 28.7 nM). Introduction of an additional methoxy group gave a derivative (3c) with nanomolar affinity (Ki = 0.7 nM), confirming the existence of a secondary binding site in the receptor which has been described previously. An increase in the affinity was also observed with the propionamido derivative 3e (Ki = 6.0 nM). The potential agonist properties of the compound 3e were evaluated on the dermal melanocytes of Xenopus laevis tadpoles. At the concentration of 2.3 nM (5 x Ki), melatonin gave a melanophore index value of 1. Similarly to melatonin, 3e was shown to be a potent agonist of the melanosome aggregation.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Compuestos Policíclicos
/
Receptores de Superficie Celular
/
Amidas
/
Melanocitos
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1996
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Estados Unidos