2,3-Dialkyl(dimethylamino)indoles: interaction with 5HT1, 5HT2, and rat stomach fundal serotonin receptors

Abstract

2,3-Dialkyl(dimethylamino)indoles, synthesized via the Fisher indole synthesis, were found to weakly bind to 5HT1 and 5HT2 sites in brain cortical membranes (IC50 greater than 1 microM at both sites for all compounds). These (dimethylamino)indoles were relatively potent antagonists of the serotonin receptor in the rat stomach fundus. At higher concentrations, several of the compounds were weak agonists at this receptor. For direct comparison with data obtained in the isolated rat fundus, antagonism of serotonin-induced contractions at 5HT2 receptors in the rat jugular vein was also examined. Several of the compounds showed good selectivity for the fundus receptor relative to the 5HT2 receptor; together with minimal affinity for 5HT1 and 5HT2 binding sites in brain cortical membranes, these results support the idea that the serotonin receptor in the stomach fundus is distinct from 5HT1 and 5HT2 binding sites.

Low Basicity as a Characteristic for Atypical Ligands of Serotonin Receptor 5-HT2

“…The most abundant group-1,3-diaryl ureas-(see Table 1: 5-HT 2A /Clusters 7 and 8, 5-HT 2B /Clusters 16 and 18, 5-HT 2C /Clusters 15 and 16) was identified by a systematic study of the impact of various indole derivatives on the serotoninergic system. The first-in-class-selective 5-HT 2C/2B receptor antagonist-SB200646A was uncovered in 1993 by previous consecutive structural modifications of 2-methyl-3-ethyl-5-(dimethylamino)-indole [34][35][36]. Since then, several series of analogues of the prototype SB200646A have been developed; i.e., derivatives of 1-(3-pyridylcarbamoyl)indolines [37][38][39][40][41], 1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo [2,3-f]indoles [42], bisaryl imidazolidin-2-ones [43], (3-methyl-5-isothiazolyl)ureas [44], diphenylureas [45] and various 1,3-biarylureas [46].…”

“…5-HT2A/Cluster 8 [37][38][39][40][41]43,45], (80 cmpds) 5-HT2A/Cluster 7 [45], (34 cmpds) pKa=5.44 pKa=8.39 [43] pKa=1.29 pKa=9.68 [58] 5-HT2A/Cluster 11 [26,50], (31 cmpds) 5-HT2A/Cluster 9 [48], (20 cmpds) pKa=0.39 pKa=7.00 [59] pKa=4.23 pKa=6.96 [48] 5-HT2A/Cluster 10 [23,26,49], (15 cmpds) 5-HT2A/Cluster 15 [60], (9 cmpds) pKa=5.88 pKa=7.00 [59] pKa=5.90 pKa=7.33 [61] 5-HT2A/Cluster 5 [62], (8 cmpds) 5-HT2A/Cluster 14 [54], (4 cmpds) pKa=3.35 pKa=8.80 [62] pKa=9.33 pKa=9.55 [63] 5-HT2B/Cluster 16 [33][34][35][36][37], (88 cmpds) 5-HT2B/Cluster 1, 2 [55], (33 cmpds) pKa=5.44 pKa=8.48 [43] pKa=5.47 pKa=9.56 [64] 5-HT2B/Cluster 22 [65] Table 1. Centroids of most populated clusters of nonbasic ligands of 5-HT2A, 5-HT2B, and 5-HT2C receptors and their structurally related basic analogues.…”

“…The most basic part of each molecule is highlighted. 5-HT2A/Cluster 8[37][38][39][40][41]43,45], (80 cmpds) 5-HT2A/Cluster 7[45], (34 cmpds) 2B /Cluster 16[33][34][35][36][37], (88 cmpds) 5-HT 2B /Cluster 1, 2[55], (33 cmpds) Centroids of most populated clusters of nonbasic ligands of 5-HT2A, 5-HT2B, and 5-HT2C receptors and their structurally related basic analogues. Compounds with overlapping cores for particular receptor subtypes share similar background color.…”

Synthesis, pharmacological and antiviral activity of 1,3-thiazepine derivatives

“…Numerous compounds containing thiourea group are selective ligands for 5-HT family receptors, including 5-HT 2A, 5-HT 2B and 5-HT 2C [13][14][15][16][17].…”

Synthesis and Pharmacological Activity of Urea and Thiourea Derivatives of 4-Azatricyclo[5.2.2.0^2,6]undec-8-ene-3,5-dione

“…[5][6][7][8][9] The drug-elicited head twitch response (HTR) 10,11) is a selective behavioral model for 5-HT 2 agonist activity in rodents, and several previous studies have established that direct and indirect 5-HT agonists induce this effect. [12][13][14][15][16][17][18][19] Additionally, 5-HT 2 receptor antagonists selectively block HTR, [19][20][21] and their potency is highly correlated with the antagonist's affinity for 5-HT 2 receptors.…”