Mapping the Melatonin Receptor. 4. Comparison of the Binding Affinities of a Series of Substituted Phenylalkyl Amides

Abstract

A series of 2-, 3-, and 4-substituted phenylalkyl amides were prepared as potential melatonin analogs in order to investigate the nature of the binding site of the melatonin receptor in chicken brain. The length of the alkyl chain was systematically varied from n = 1 to 4, and methoxyl substituents were incorporated into the phenyl ring at the 2-, 3-, and 4-positions. The maximum binding affinity was found to occur when n = 3 and when the methoxyl substituent was in the 3-position, the direct analog of the carbon framework of melatonin in which the 1,2-atoms of the indole ring have been removed. Whereas there was only a relatively small decrease in binding affinity for the corresponding 2-methoxy derivatives, 4-methoxyl substitution led to a large decrease in binding affinity, suggesting that the binding sites for the side chain and methoxyl group could not now be occupied at the same time. As in the indole analogs of melatonin, replacement of the methyl group of the amide by a longer alkyl chain led to an increase in binding affinity for ethyl and propyl with a subsequent decrease in binding affinity for butyl chains. Thus N-propanoyl-3-(3-methoxyphenyl)propanamine (6f) has a binding affinity of 5.6 nM, a remarkably high affinity for so simple a compound. Substitution of halogen for 3-methoxyl in the propanamide series gave a series of compounds with lower, but still substantial, binding affinities, the 3-chloro derivative 7e showing the highest affinity, 113 nM. In the case of the 3-fluoro propanamides, a maximum in the binding affinity was not observed in the series synthesized, and these derivatives will merit further exploration. These results demonstrate the utility of simple, readily modified phenylalkylamines as a "framework" for studying the effect of changes in the nature and position of substituents on the melatonin receptor binding affinity.

Analogues of diverse structure are unable to differentiate native melatonin receptors in the chicken retina, sheep pars tuberalis and Xenopus melanophores

“…Compounds 15-17 are methoxy substituted phenylalkylamides (Garratt et al, 1996). Only N-acetyl 3-methoxy-l-(3-aminopropyl)benzene (16), a direct analogue of melatonin, in which the N-and C-1-carbon atoms of the indole ring have been removed, possessed any agonist activity, and had the highest affinity of the three analogues in the binding assays.…”

“…N-Acetyltryptamine (12), N-acetyl 2-phenyltryptamine (13), N-acetyl 2-bromotryptamine (14), N-propanoyl 5-methoxytryptamine (3), N-acetyl 3-amino-6-methoxy-1,2,3,4-tetrahydrocarbazole (19) and N-acetyl 4-aminomethyl-6-methoxy-9-methyl-1,2,3,4-tetrahydrocarbazole (20) were synthesized as described previously (Garratt et al, 1994a,b;1995). N-Acetyl 2-methoxy-1-(3-aminopropyl)benzene (15), Nacetyl 3-methoxy-l-(3-aminopropyl)benzene (16) and N-acetyl 4-methoxy-l-(3-aminopropyl)benzene (17) were synthesized from commercially available 3-(X-methoxyphenyl)propionic acids (Garratt et al, 1996). Finally, N-formyl 5-methoxytryptamine (1), N-butanoyl 5-methoxytryptamine (4), N-cyclopropanecarbonyl 5-methoxytryptamine (5) N-acetyl 5-methoxychroman (21), N-acetyl 5-benzyloxytryptamine (9) Nacetyl 5-methyltryptamine (10) were synthesized from the free amines, 5-methoxy and 5-methyltryptamine (Sigma) or 3-amino-5-methoxychroman (generously supplied by Dr SethOlov Thorberg, Astra Alab AB, Sodertalje, Sweden), as described previously (Ho et al, 1968;Sugden, 1994 (Figure 1).…”

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).…”

Recent Advances in Melatonin Receptor Ligands

“…The (±)-methoxychroman 8 exhibited also only modest affinity for the melatonin receptor in chicken brain, being 160-fold less potent than melatonin [53]. The S-(Ϫ)-enantiomer of the aminomethyltetrahydrocarbazole 9 was reported to possess comparable affinity to melatonin for the receptor in chicken brain [54,55]. A higher degree of conformational restriction of the amido side chain was achieved in a series of benzoindoles [56] and phenalenes [57,58], exemplified by compounds 10Ϫ13 and 14Ϫ15, respectively.…”