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

Abstract

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 mt(1) and MT(2) 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 (7a-d) showed much higher binding affinities than the parent isoindoles (5a-e), and whereas 7a-c were agonists in the functional assay, 7d and 5a-e were antagonists. The 2-ethoxyisoindolo[2,1-a]indoles (10a-d) 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 (21a-c) had higher binding affinities than the corresponding parent indoloisoquinolines (20a-c) 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 (25a-d) had higher binding affinities than the corresponding parent compounds (23a-d) at the MT(2) receptor but similar affinities at the mt(1) 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 MT(2) receptor. All of the derivatives investigated had either the same or a greater affinity for the human MT(2) receptor compared to the mt(1) receptor (range 1:1-1:132). This suggests that the mt(1) and MT(2) 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 mt(1) and MT(2) melatonin receptors. Compound 7c is a potent agonist with some selectivity (44-fold) for the MT(2) receptor, while 25c is an MT(2)-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.

Synthesis of N1-Phenethyl Substituted Indole Derivatives as New Melatoninergic Agonists and Antagonists.

“…The introduction of the methoxyl group at C-5 did not lead to the expected decrease in the antagonistic activity of molecules 9b, d and e (Table 1). This is in contrast to the biological data obtained on the previously reported analogous tetracyclic compounds 2a-h. 23) The exception observed in the full agonist activity of compound 9c could be attributed to a synergistic effect caused by the presence of the 5-OMe group and the size of the acyl group (RϭC 3 H 7 ). The simultaneous incorporation of both of these moieties to indole analogs is known to drastically enhance melatoninergic agonistic activity.…”

“…3-Indolylacetonitrile (4a) and 5-methoxyindole-3-acetonitrile 24) (4b) were separately reacted with the tosylate 5, prepared from 2-phenylethanol and p-toluenesulfonyl chloride (TsCl), 23) to give the N-alkylated acetonitriles 6a and b, respectively. These were reduced with lithium aluminun hydride in the presence of diethyl ether and benzene (5 : 1 v/v) 25) to afford the corresponding amines 7a and b, which were not purified but were immediately acylated with the appropriate reagent 23) to give…”

“…5-Methoxyindole-3-carboxaldehyde (10) was condensed with the tosylate 5 to furnish aldehyde 11 and the sequence of the Henry reaction 23) with nitroethane followed by reduction 23) gave the amine 13, which was acylated with the appropriate reagent 23) to give the desired N-{2- [5-…”

“…2. 23) In the Xenopus melanophore pigment aggregation model, compounds 1a-j were found to exhibit agonist activity while their congeners 3a-j were antagonists. Molecules 2a-d were antagonists and 2e-h had agonist activity at low concentrations but antagonised responses at high concentrations, Fig.…”

Modern Friedel-Crafts chemistry. Part 35. New synthetic approach to substituted indolo[2,1-a][2]benzazepines and indolo[2,1-a]isoquinolines via Friedel-Crafts cyclialkylations

“…[2]benzazepine (1) 4 and 6,7-dihydroindolo[2,1-a]isoquinoline (2) [5][6][7] have unique nitrogen-containing tetracyclic 8 structures (Scheme 1). Their analogues occur widely in isolated natural products 9 , in drugs 10 and the derived π-conjugated materials are used as organic semiconductors.…”