Synthesis of a Novel Series of Benzocycloalkene Derivatives as Melatonin Receptor Agonists

• Published in: Journal of medicinal chemistry 2002-09, Vol.45 (19), p.4212-4221
• Main Authors: Fukatsu, Kohji, Uchikawa, Osamu, Kawada, Mitsuru, Yamano, Toru, Yamashita, Masayuki, Kato, Koki, Hirai, Keisuke, Hinuma, Shuji, Miyamoto, Masaomi, Ohkawa, Shigenori
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Binding Sites; Biological and medical sciences; CHO Cells; Cricetinae; Humans; Indenes - chemical synthesis; Indenes - chemistry; Indenes - pharmacology; Male; Medical sciences; Melatonin - metabolism; Mesocricetus; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Organ Specificity; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Radioligand Assay; Receptors, Cell Surface - agonists; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Melatonin; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020114g

We synthesized a novel series of benzocycloalkene derivatives and evaluated their binding affinities to melatonin receptors. To control the spatial position of the amide group, one of the important pharmacophores, we incorporated an endo double bond, an exo double bond (E- and Z-configurations), and a chiral center (R- and S-configurations) at position 1. The indan derivatives with the S-configuration at position 1 were the most promising in terms of potency and selectivity for the human melatonin receptor (MT1 site), while compounds with the R-configuration showed little potential. Our next attempt was to investigate the most favorable conformation of the methoxy group, the other important pharmacophore for binding to the MT1 receptor. The introduction of a methyl group at position 5 of the indene ring conserved affinity; however, at position 7, it caused a decrease in affinity. These results suggested that the substitution at position 7 forced the methoxy group to adopt an unfavorable orientation. The optimization of the condensed ring size and substituents led to (S)-8d [(S)-N-[2-(2,3-dihydro-6-methoxy-1H-inden-1-yl)ethyl]propionamide], which had high affinity for the human MT1 receptor (K i = 0.041 nM) but no significant affinity for the hamster MT3 receptor (K i = 3570 nM). In addition, a practical synthetic method of chiral N-[2-(2,3-dihydro-1H-inden-1-yl)ethyl]alkanamides employing asymmetric hydrogenation with (S)-2,2‘-bis(diphenylphosphino)-1,1‘-binaphthyl−Ru has been established.