Novel 2-substituted tetrahydro-3H-benz[e]indolamines: highly potent and selective agonists acting at the 5-HT1A receptor as possible anxiolytics and antidepressants

Abstract

The synthesis of (+)-(R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H- benz[e]indole [(R)-14, U92016A], a potent 5-HT1A agonist, and related analogs is described. In vitro binding studies show that the (R)-enantiomers of this series possess the highest potency for the 5-HT1A receptor. In vivo hypothermia correlates with this, with the (R)-enantiomers causing a greater temperature drop than the (S)-enantiomers. The most active compound in 5-HT1A binding and in the in vivo models was (R)-14, which was found to be highly potent as an agonist in single cell firing studies, as well as potent and of very high intrinsic activity in mouse hypothermia and the sympathetic nerve discharge (SND) models. An in vivo duration of action study, following SND, showed (R)-14 to possess a long duration of action. The synthesis via a nitrene insertion, determination of absolute configuration, and biological activities of this series is described.

Derivatives as 5HT1A Receptor Ligands-Past and Present

“…The enantiomers and racemates of 27 and 28 were evaluated for their affinities to the 5-HT 1A receptor sites and in agreement with the biochemical and behavioural data. The Also, substitution at the C-2 of the pyrrole with a carboxamide (34) or cyano UH92016A -35 function is favourable for 5-HT 1A affinity [54]. In fact, compound (+)-…”

Intravenous buspirone for the prevention of postoperative nausea and vomiting

“…Extrapolating dose from animal to man is difficult. For example, the published K I value for buspirone against D2 is some tenfold higher in the rat [19] than in humans [20], although this does not necessarily mean the same is true in any other small mammal species. The pharmacokinetics and binding affinity of buspirone for the D 2 and 5HT 1A receptors in the ferret are unknown and may be very different from those in humans.…”

Structure-Activity Relationships in the 8-Amino-6,7,8,9-tetrahydro-3H-benz[e]indole Ring System. Part 1: Effects of Substituents in the Aromatic System on Serotonin and Dopamine Receptor Subtypes

“…The resulting precipitate was filtered off, and the solution was evaporated to a residue of 25 mg (94%) of pure product. The fumarate salt was prepared and recrystallized from methanol/diethyl ether: mp 188-191 °C (fumarate); NMR (300 MHz, CDCI3) 0.90 (t, 6H), 1.50 (sxt, 4H), 1.65 (m, 1H), 2.05 (br s, 1H), 2.50 (s, 3H), 2.55 (t, 4H), 2.93 (dd, 2H), 3.0-3.2 (m, 2H), 3.52 (m, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.87 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.9 (br s, 1H); MS m/e 284 (M+, 50), 184 (100), 255 (68), 157 (36), 168 (11). Anal.…”

“…Compounds 9 and 10 were less potent. In the same article it was found that the isosteric (to 4) 8-(dipropylamino)-6,7,8,9-tetrahydrobenz[g]indole (11) and analogs were inactive at 5-HTia receptors. Furthermore, the IV-formylindoline 12, which is easily superimposed on 5 and thus would seem to mimic 5, was almost inactive at 5-HTia receptors.…”

“…The low affinities of compounds 11 and 12 raised questions concerning the importance of the indole NH moiety for the affinity for this type of compound, which would also be a subject of this investigation. In addition, we wanted to see if a small alteration in the 4-position (corresponds to 6-position in aminotetralins) would affect the in vivo and in vitro profile.…”