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Mapping the Melatonin Receptor. 6. Melatonin Agonists and Antagonists Derived from 6H-Isoindolo[2,1-a]indoles, 5,6-Dihydroindolo[2,1-a]isoquinolines, and 6,7-Dihydro-5H-benzo[c]azepino[2,1-a]indoles

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Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K.
Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens, Panepistimiopolis-Zografou, Athens 157 71, Greece
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens 116 35, Greece
Physiology Division, School of Biomedical Sciences, New Hunts House, King's College London, Guy's Campus, London SE1 1UL, U.K.
Cite this: J. Med. Chem. 2000, 43, 6, 1050–1061
Publication Date (Web):March 23, 2000
https://doi.org/10.1021/jm980684+
Copyright © 2000 American Chemical Society

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    Abstract

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    6H-Isoindolo[2,1-a]indoles (5, 7, 10, 13), 5,6-dihydroindolo[2,1-a]isoquinolines (20, 21), and 6,7-dihydro-5H-benzo[c]azepino[2,1-a]indoles (23, 25, 27, 30) 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 mt1 and MT2 receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores. The 2-methoxyisoindolo[2,1-a]indoles (7ad) showed much higher binding affinities than the parent isoindoles (5ae), and whereas 7ac were agonists in the functional assay, 7d and 5ae were antagonists. The 2-ethoxyisoindolo[2,1-a]indoles (10ad) showed reduced binding affinities compared to their methoxy analogues, while the 5-chloro derivative 13 showed a considerable reduction in binding affinity and potency compared to 7a. The 10-methoxy-5,6-dihydroindolo[2,1-a]isoquinolines (21ac) had higher binding affinities than the corresponding parent indoloisoquinolines (20ac) in the human receptor subtypes, and the parent compounds were antagonists whereas the 10-methoxy derivatives were agonists in the functional assay. The N-cyclobutanecarbonyl derivatives of both the parent (20d) and 10-methoxyl (21d) series had similar binding affinities and were both antagonists with similar potencies. The 11-methoxy-6,7-5H-benzo[c]azepino[2,1-a]indoles (25ad) had higher binding affinities than the corresponding parent compounds (23ad) at the MT2 receptor but similar affinities at the mt1 site; all of the compounds were antagonists in the functional assay. Changing 11-methoxy for 11-ethoxy decreased the binding affinity slightly, and this was more evident at the MT2 receptor. All of the derivatives investigated had either the same or a greater affinity for the human MT2 receptor compared to the mt1 receptor (range 1:1−1:132). This suggests that the mt1 and MT2 receptor pockets differ in their ability to accommodate alkyl groups in the indole nitrogen region of the melatonin molecule. Two compounds (7c and 25c) were tested in functional assays on recombinant mt1 and MT2 melatonin receptors. Compound 7c is a potent agonist with some selectivity (44-fold) for the MT2 receptor, while 25c is an MT2-preferring antagonist. Increasing the carbon chain length between N-1 of indole and the 2-phenyl group from n = 1 through n = 3 leads to a fairly regular decrease in the binding affinity, but, remarkably, when n = 3, it converts the methoxy compounds from melatonin agonists to antagonists. The Xenopus melatonin receptor thus cannot accommodate an N-n-alkyl chain attached to a 2-phenyl substituent with n > 2 in the required orientation to induce or stabilize the active receptor conformation.

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