Search for a 5-CT alternative. <i>In vitro</i> and <i>in vivo</i> evaluation of novel pharmacological tools: 3-(1-alkyl-1<i>H</i>-imidazol-5-yl)-1<i>H</i>-indole-5-carboxamides, low-basicity 5-HT₇ receptor agonists

Abstract

Close structural analogues of 5-carboxamidotryptamine (5-CT) based on the newly discovered indole-imidazole scaffold were synthesized and evaluated to search for a 5-HT₇ receptor agonist of higher selectivity. <i>In vitro</i> drug-likeness studies and <i>in vivo</i> pharmacological evaluation of potent and selective low-basicity 5-HT₇ receptor agonists, previously published <b>7</b> (3-(1-ethyl-1<i>H</i>-imidazol-5-yl)-1<i>H</i>-indole-5-carboxamide, AH-494) and <b>13</b> (3-(1-methyl-1<i>H</i>-imidazol-5-yl)-1<i>H</i>-indole-5-carboxamide), have supported their usefulness as pharmacological tools. Comprehensive <i>in vitro</i> comparison studies between <b>7</b>, <b>13</b> and the commonly used 5-CT showed their very similar ADMET properties. Compound <b>7</b> at 1 mg kg^-1 reversed MK-801-induced disruption in novel object recognition in mice and alleviated stress-induced hyperthermia (SIH) at high doses. Taking into account both <i>in vitro</i> and <i>in vivo</i> data, <b>7</b> and <b>13</b> may be considered as alternatives to 5-CT as pharmacological tools with important additional benefit associated with their low-basicity: high selectivity over 5-HT_1AR.