title: Selective, centrally acting serotonin 5-HT2 antagonists. 1. 2- and 6-substituted 1-phenyl-3-(4-piperidinyl)-1H-indoles.
abstract: A series of 1-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-imidazolidinones has been synthesized. The 1-position of the indole is substituted with phenyl groups and in the 2- or 6-positions are additional substituents. An analogous series with the imidazolidinone ring opened to corresponding urea derivatives was also prepared. High potency and selectivity for 5-HT2 receptors (as compared with D2 and alpha 1 receptor affinities) were obtained with medium-large substituents such as 6-chloro, 6-methyl, and 6-trifluoromethyl or a 2-methyl substituent. Larger 6-substituents such as isopropyl considerably reduced activity, while the smaller 6-fluoro substituent afforded unselective compounds. Selective 5-HT2 antagonists were found by combining 6-substitution with both unsubstituted 1-phenyl and substituted 1-phenyl groups (2-F, 4-F, 4-Cl). However, 3-substitution of the phenyl group markedly reduced 5-HT2 receptor affinity, especially with a 3-trifluoromethyl substituent. Introduction of a 3-(2-propyl) substituent in the imidazolidinone ring reduced binding to alpha 1 adrenoceptors with a factor of 3-8. Practically no influence on 5-HT2 and D2 receptor affinities were found by the presence of this substituent compared to the 3-unsubstituted derivatives. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and they had a long duration of action (> 24 h). Especially urea derivatives were found to be considerably more potent at 24 h than at 2 h after subcutaneous administration. Some of the compounds potently inhibited isolation-induced aggression in mice, an effect which, however, did not correlate to 5-HT2 receptor-mediated activities. On the basis of these structure-activity studies 1-[2-[4-[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1- piperidinyl]ethyl]-3-(2-propyl)-2-imidazolidinone (Lu 26-042, compound 4c) was selected for further pharmacological and toxicological investigations.
authors.affiliation: H. Lundbeck A/S, Cophenhagen-Valby, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Perregaard
authors.forename: K
authors.initials: K
authors.lastname: Andersen
authors.forename: J
authors.initials: J
authors.lastname: Hyttel
authors.forename: C
authors.initials: C
authors.lastname: Sánchez
mesh_terms: D000818:Animals; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D007211:Indoles; D010880:Piperidines; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists