Behavioral studies on the enantiomers of butaclamol demonstrating absolute optical specificity for neuroleptic activity

Abstract

Butaclamol is a member of a new chemical class for which antipsychotic activity in humans has been demonstrated. Butaclamol, a racemate, has been resolved into its optical isomers and a separation of activities was found to occur between the (+) and (-) enantiomers. The present experiments show that at doses ranging from 0.1 to 0.3 mg/kg the (+) enantiomer abolished amphetamine-induced (a) stereotyped behavior and (b) rotational behavior in rats with unilateral lesions in the substantia nigra. It also inhibited the lever-pressing response in the continuous (Sidman) avoidance procedure, blocked discriminated avoidance behavior, and decreased ambulation and rearing in the open field. In contrast, the (-) enantiomer was devoid of behavioral activity at 100-500 times larger doses. At considerably higher doses (+)-butaclamol antagonized epinephrine-induced mortality. Again, the (-)-butaclamol was devoid of this activity as well. The significance of absolute optical specifity manifested by a neuroleptic drug is discussed in the light of dopaminergic and adrenergic mechanisms.

Neuroleptic-induced attenuation of brain stimulation reward in rats.

“…Drugs. Two drugs, pimozide (Janssen Pharmaceuticals) and (+)-butaclamol (Ayerst Laboratories), were used to examine the effects of dopamine receptor blockade (Andfo, Butcher, Corrodi, Fuxe, & Ungerstedt, 1970;Creese, Burt, & Snyder, 1976;Lippman & Pugsley, 1975;Voith & Cummings, 1976;Voith & Herr, 1975). The effects of norepinephrine receptor blockade were examined with phenoxybenzamine (Smith Kline & French Canada, Ltd.), an agent that blocks central receptors of the a-noradrenergic type (Andto & Strombom, 1974;Nickerson & Collier, 1975).…”

Chiral analysis of butaclamol enantiomers in human plasma by HPLC using a macrocyclic antibiotic (vancomycin) chiral stationary phase and solid phase extraction

“…(+)-Butaclamol is an effective antipsychotic agent but ( -)-butaclamol is devoid of this activity. 18 The only published method for analysis of racemic butaclamol in serum is by TLC -fluorometric induction. The method involved cyclohexane extraction of serum samples followed by TLC of the concentrated extracts.…”

Mapping the dopamine receptor. 1. Features derived from modifications in ring E of the neuroleptic butaclamol

“…It has been shown that in this series 1 neuroleptic activity is associated with 4a,13b-trans and 3(OH),13b(H)-trans relative configurations1,4,12 and that only the enantiomers having 3S,4aS,13bS absolute configurations are active. 4,5,12 We have described the qualitative and quantitative changes in neuroleptic activity which result from altering the bulky substituent at position 3,1,2 by introducing a chlorine substitutent at various positions on rings A and C3, and, in the following paper of this issue,13 from making molecular modifications in the rings A/B region.…”

“…16 Reduction of 2 with sodium borohydride gave a 73% yield of the secondary alcohol 4, while reduction with lithium tri-sec-butylborohydride17 afforded 66% of the epimeric alcohol 5. The configurational assignments for Scheme I HO 4 [3(H),13b(H)-trans] 5 [3(H),13b(H)-cis] 2 (4a,13b-trans) 3 (4a,13b-cis) 5, as 3(H),13b(H)-cis (hydroxyl axial), and for 4, therefore, as 3(H),13b(H)-trans (hydroxy equatorial), are based on the report18 that the bulky tri-sec-butylborohydrides reduce cyclohexanones by virtually exclusive attack by the reagent from the equatorial side to produce axial alcohols.…”