Antipsychotic activity of substituted .gamma.-carbolines

Abstract

Several novel substituted gamma-carbolines were synthesized and examined in a series of in vitro and in vivo pharmacological tests to determine potential antipsychotic activity. Most compounds were orally active in blocking the conditioned avoidance response (CAR) in rats but did not antagonize apomorphine-induced stereotyped behavior. Compound 17 (Wy-47,384), a gamma-carboline with a 3-(3-pyridinyl)propyl side chain, was selected for development as an atypical antipsychotic agent because of its potent and selective profile in preclinical psychopharmacological tests. It blocked CAR in rats with an AB50 of 14 mg/kg po, showed weak affinity for the D2 receptor site (Ki = 104 nM), and showed differential potency in antagonizing apomorphine-induced stereotyped behavior (ED50 = 11 mg/kg ip) and climbing behavior (ED50 = 4 mg/kg ip). Such activities are suggestive of antipsychotic efficacy combined with a low potential for extrapyramidal side effect (EPS) liability.

Modification of Hypothalamic- Pituitary-Adrenocortical Activity by Serotonergic Agents in the Rat

“…For example, buspi rone and carvotroline also demonstrate an affinity for the dopamine D? receptor [20,24] and enciprazine has an affinity for the aiadrenergic receptor [25]. One observed differ ence was that enciprazine and carvotroline showed decreased corticosterone levels at lower doses, e.g.…”

γ-Carbolines and their hydrogenated derivatives. 2.* Hydrogenated derivatives of γ-carbolines: methods of synthesis (review)

“…For example, the Mannich base 47, obtained from methylaminoacetaldehyde acetal, readily undergoes cyclization in HCl solution to the corresponding 4-hydroxy derivative, which can then be easily reduced to 4-unsubstituted tetrahydro-γ-carboline [102]. EtOH, 25°C, 16 h N-β-Hydroxyethyl derivatives of 3-aminomethylindole 48 [103], synthesized from 3-formylindole and the respective amino alcohol by reductive amination [104], also undergo acid-catalyzed intramolecular cyclization with the formation of 1,2,3,4-tetrahydro-γ-carbolines. inversion Evidence in favour of the proposed mechanism with the formation of the intermediate 50 can be obtained from the formation of the tetrahydro-γ-carbolines 51a,b as side products during an attempt to synthesize 1,4-diaryl-substituted tetrahydro-β-carbolines 52a,b from the corresponding aryltryptamines 53a,b by the Pictet-Spengler reaction [106].…”

Synthesis and in vitro evaluation of 4-substituted furano[3,2-c] tetrahydroquinolines as potential anti-cancer agents

“…Tetrahydroquinolines are common structures and a very important class of bioactive heterocycles 1 , which show neuroleptic 2 , antipsychotic 3 , antagonistic 4,5 , antimalarial 6,7 , antitumor 8,9 , anti-HIV 10 , antibacterial 11 , anti-allergic 12 , and anti-inflammatory activities 13 . In addition, 4-heteroaromatic substituted anilines are another class of bioactive heterocycles with antitumor activity.…”