Design and Synthesis of Naphthalenic Dimers as Selective MT₁Melatoninergic Ligands

Abstract

We report the synthesis and binding properties at MT(1) and MT(2) receptors of the first example of agomelatine (N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide) dimers in which two agomelatine moieties are linked together through their methoxy substituent by a polymethylene side chain according to the "bivalent ligand" approach. Some of these compounds behave as MT(1)-selective ligands. The most selective one (5) behaves as an antagonist.

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…MELATONIN RECEPTORS analog of melatonin, are linked together through their methoxy substituent by a polymethylene side chain (Descamps-François et al, 2003). The number of methylene groups in the linking chain varied from 2 to 8; the highest selectivity ratio was for three methylene groups (S 26131).…”

Physiological and metabolic functions of melatonin

“…Most of them are MT2 selective (33,59,103,6). Recently, the first MT1 selective ligands have been reported (29). The selective MT2 melatonin ligands have yet lead to the identification of some specific functions of MTi and MT2 receptor subtypes and studies on cells expressing only one of the subtypes have given information on the signaling (62).…”

Paradigms and paradoxes: Mechanisms for possible enhanced biological activity of bilaterally symmetrical chemicals

“…The effectiveness of these agents is related to the disparity between compounds possessing one vs two quaternary nitrogens. Inhibitors possessing bilateral symmetry are composed of two like parts and may have an entropic advantage over acetylcholine (5) evolved, since proteins are specialized for structure-based stability relationships with natural molecules [4]. Scheme 2 shows the amino acid residues located in acetylcholine esterase.…”

“…For example, a C 2 symmetric molecule can attach to the crystal in two ways. Literature values for the melting points of CF 4 [5]. The binding of CF 4 to the crystal is influenced by the symmetry number, but also the molecular weight to determine its rate of release from the crystal, determined by melting points.…”