Design and Synthesis of New Naphthalenic Derivatives as Ligands for 2-[125I]Iodomelatonin Binding Sites

Abstract

New melatonin-like agents were designed from the frameworks of 2,5-dimethoxyphenethylamine, an important structural moiety for the 5-HT receptor, and (2-methoxynaphthyl)-ethylamine. The compounds were synthesized by classical methods and evaluated in binding assays with chicken brain membranes using 2-[125I]iodomelatonin as the radioligand. Preliminary studies on the series of N-acyl-disubstituted phenethylamines showed the favorable role of the methoxy group in the ortho position of the side chain on the affinity for the receptor (Ki = 8 +/- 0.2 nM) for N-[2-(2-methoxy-5-bromophenyl)ethyl]propionamide (3o). This effect was confirmed in a series of the naphthalene derivatives, a bioisosteric moiety of the indole ring, and several potent ligands for melatonin binding sites were prepared such as N-[2-(2-methoxynaphthyl)ethyl]propionamide (4b) (Ki = 0.67 +/- 0.05 nM) and N-[2-(2,7-dimethoxynaphthyl)ethyl]cyclopropylformamide (Ki = 0.05 +/- 0.004 nM) (4k). Structure-activity relationships are discussed with regard to melatonin and bioisosteric naphthalenic compound 2. The Ki value for 4b was affected to a similar extent to that of melatonin by GTP-gamma-S or Mn2+ in competition experiments, suggesting an agonist profile for this compound.

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

“…The 5-position on the indole ring is optimal for the methoxy group, because moving it to position 4, 6, or 7 leads to a dramatic loss of affinity, although compounds with a halogen at the 5-position do retain high affinity (Mor et al, 1998). The relative position of the methoxy group and the N-acetylaminoethyl side chain seems to be an important determinant of affinity (Depreux et al, 1994;Langlois et al, 1995;Garratt et al, 1996). The indole ring is not essential for ligand binding because it can be replaced by various other aromatic systems such as naphthalene, benzofuran, benzothiophene, or benzocycloalkene rings (Depreux et al, 1994;Leclerc et al, 1998;Fukatsu et al, 2002).…”

New substrate analogues of human serotonin N‐acetyltransferase produce in situ specific and potent inhibitors

“…Indeed, our data suggest that they are acetyl-CoA binding, as well as substratebinding site competitive inhibitors because they occupy the cosubstrate site. As these compounds are broad analogues of melatonin [16][17][18][19][20][21][22][23][24][25], we report their affinities for the MT 1 and/or MT 2 receptors.…”

Synthesis and Pharmacological Analysis of High Affinity Melatonin Receptor Ligands.

“…Currently, what we know is that the indole ring of melatonin is not crucial for melatonin receptor recognition. For instance, the naphthalene ring [11][12][13][14][15][16][17][18][19][20] can serve as a bioisostere of the indole nucleus of melatonin and analog 2 was reported to have equivalent affinity to melatonin for melatonin receptors in ovine pars tuberalis.…”

“…Currently, what we know is that the indole ring of melatonin is not crucial for melatonin receptor recognition. For instance, the naphthalene ring [11][12][13][14][15][16][17][18][19][20] can serve as a bioisostere of the indole nucleus of melatonin and analog 2 was reported to have equivalent affinity to melatonin for melatonin receptors in ovine pars tuberalis.11) In addition, other groups such as amidotetralin, 21) methoxychroman, 22) amido indane, 23) benzofuran, 18,24) benzothiophene 18,24) and quinoline 25) can serve as a bioisostere of the indole nucleus of melatonin. Langlois et al reported that the addition of a 2-methoxy group (OMe) to compound 2 to form 3 results in an order of magnitude increase in receptor affinity over compound 2 (Fig.…”

“…1). 12) After eliminating the steric interference of the amidoethyl side chain and the substituents on 2-position, we then synthesized compounds 6-10 with the substituents on 7-position of varying sizes.…”