SYNTHESIS OF 2-AMIDO-2,3-DIHYDRO-1H-PHENALENE DERIVATIVES AS NEW CONFORMATIONALLY RESTRICTED LIGANDS FOR MELATONIN RECEPTORS

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 su ccinic 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 correspondin g alpha-N-acetyl amino acids. The ketone derivatives were reduced dire ctly by catalytic hydrogenation to produce the compounds 3. The differ ent compounds were evaluated in vitro in binding assays using 2-[I-125 ]iodomelatonin and chicken brain membranes. Melatonin and 2-acetamido- 8-methoxytetralin were used as the reference compounds. The results sh owed the superiority of the dihydrophenalene framework 3 over tho se o f tetrahydro anthracene and tetrahydrophenanthrene. 3a had relatively good affinity for melatonin receptors (K-i = 28.7 nM). Introduction of an additional methoxy group gave a derivative (3c) with nanomolar aff inity (K-i = 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 (K-i = 6.0 nM). The potential agonist properties of the compound 3e we re evaluated on the dermal melanocytes of Xenopus laevis tadpoles. At the concentration of 2.3 nM (5 x K-i), melatonin gave melanophore inde x value of 1. Similarly to melatonin, 3e was shown to be a potent agon ist of the melanosome aggregation.