Mapping the Melatonin Receptor. 7. Subtype Selective Ligands Based on β-Substituted N-Acyl-5-methoxytryptamines and β-Substituted N-Acyl-5-methoxy-1-methyltryptamines

Abstract

A series of beta-substituted and beta,beta-disubstituted N-acyl 5-methoxy-1-methyltryptamines and 5-methoxytryptamines have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human MT(1) and MT(2) receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency of all analogues was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores. beta-Methylmelatonin (17a) and beta,beta-dimethylmelatonin (17b), though showing a slight decrease in binding at human receptors, show an increase in potency on Xenopus. N-Butanoyl 5-methoxy-1-methyl-beta,beta-trimethylenetryptamine (12c) is an antagonist at human MT(1) receptors but an agonist at MT(2), while N-butanoyl 5-methoxy-1-methyl-beta,beta-tetramethylenetryptamine (13c) is an antagonist at MT(1) but had no action at MT(2) and is one of the first examples of an MT(1) selective antagonist.

A New, Stereoselective, Ring-Forming Reaction of 1,2-Ethanedithiol with N-Acylated Indoles

“…According to the proposed mechanism, the catalyst (BF 3 This new cyclization proceeds with very high stereoselective control to afford an N1-C2 annulated indoline as a single diastereomer. We are now examining the application of this reaction to other N-heterocycles and are investigating the reactions of these dithiazepines, which represents a relatively unknown system.…”

“…3 We prepared the 4-fluoroindole analogue 3 (Scheme 1) in 40% yield by standard treatment of the ketone 2 with 1,2-ethanedithiol and boron trifluoride etherate. Compound 3 was a modest melatonin antagonist (pIC 50 ) 4.96 nM) 4 with some selectivity (11-fold) for the MT 2 receptor.…”

Design and Synthesis of New N1 and C3-Substituted 4-Fluoroindolic Melatoninergics

“…During the last fifteen years, we [18] and others [19] have sought to understand how melatonin binds to and activates these receptors using both indole and non-indole derivatives. The 5-methoxy group of melatonin has been shown to be important for binding to the receptor [20,21], but it is not an essential requirement for agonist activity [22].…”

“…The indole core of the hormone is also not required, provided that the N-alkanamido side chain is linked to an appropriate aromatic spacer, which can be benzene itself [23,24]. The active conformation of the 3-ethanamide side chain has been established from studies with conformationally restricted indole [22,25] and non-indole analogues [18,24,[26][27][28][29]. The conformational preferences of jet-cooled melatonin have recently been explored, and the active conformation is one of the four lowest minima [30].…”

“…Having recently shown that -substituents in the side chain of N-acyl tryptamines enhance potency and MT 1 selectivity [18], we introduced in the skeleton of 4a-d a -ketone and a dithiolano group (4e). Furthermore, we retained the C-4 fluorine atom in the carbocyclic ring because of its unique properties due to which the biological half life of synthetic compounds is extended and the formation of toxic metabolites is nearly eliminated.…”