SEARCH · PubMed Health

Results for “Butaclamol”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed1985

The pKa of butaclamol and the mode of butaclamol binding to central dopamine receptors.

The pKa values for butaclamol (1), 1,2,3,5,6,10b beta-hexahydro-6 alpha-phenylpyrrolo[2,1-alpha]isoquinoline (2, McN-4612-Y), and 2-tert-butyl-1,3,4,6,7,11b beta-hexahydro-7 beta-phenyl-2H-benzo[alpha]quinolizin-2 alpha-ol (3, McN-4171) were determined to be 7.2, 9.1, and 7.0, respectively. The values for 1 and 3 are anomalous; however, the value for 1 (7.2) is not as low as the one reported in the literature (pKa = 5.9). We also determined pKa values for apomorphine, chlorpromazine, and lidocaine, for reference purposes (7.6, 9.2, and 7.9, respectively). The results indicate that 1 would not be predominantly unprotonated under the physiological conditions of receptor binding, rather it would be about 50% protonated. This fact may contravene a suggested binding model used to map the central dopamine receptor (viz., ref 3).

Animals↗

PubMed1984

[Effect of butaclamol enantiomers on hypothalamic tyrosine hydroxylase in the rat brain].

The authors demonstrate stereospecificity of the action of butaclamol enantiomers on substrate inhibition of hypothalamic tyrosine hydroxylase (TH) and regulation of the tyrosine hydroxylase response by the presynaptic membrane (presynaptic receptors) of rat hypothalamus synaptosomes under membrane activation with dopamine. The effect of (+)-butaclamol on the substrate inhibition of TH was noticeable at a concentration of 10(-8)M, reaching a maximum at 10(-5)M. (-)-Butaclamol administered at the same concentrations did not influence the substrate inhibition of the enzyme. (+)-Butaclamol added to the incubation medium containing hypothalamic synaptosomes concurrently with dopamine (10(-5)M) completely blocked the regulatory action of the latter on TH, with this action mediated via presynaptic receptors. (-)-Butaclamol (10(-5)M) antagonized the action of dopamine under the same conditions. The data obtained indicate high stereo-specificity of butaclamol enantiomers as regards their effect on presynaptic regulation of TH, suggesting that elimination of the substrate inhibition of hypothalamic TH is a stereoselective effect of neuroleptics and can be a prognostically important criterion in the appraisal of compounds with potential neuroleptic activity.

Animals↗

PubMed1983

Conformational properties of butaclamol and isobutaclamol. Regularities in the structures of semirigid neuroleptics.

Conformational energy calculations have been performed on butaclamol and isobutaclamol using Allinger's MM2 (Molecular Mechanics II) program. Cis arrangements of rings D and E were found to be preferred by 1.4-1.9 kcal/mole for both compounds. Nevertheless, based on a molecular comparison with a number of semirigid neuroleptics, most notably loxapine and octoclothepin, it is suggested that trans arrangements are required for neuroleptic activity in the two compounds. However, trans conformer B of butaclamol, which was previously postulated as the biologically active form, was found to be 4.1 kcal/mole higher in energy, suggesting that it is less likely to play a significant pharmacological role. The biologically active forms are identified as trans conformer A for butaclamol and trans conformer B for isobutaclamol. Certain regularities in the structures of the semirigid neuroleptics are noted. It is also speculated that the cis conformers of protonated butaclamol may have unfavorable geometries for ion solvation, which would account for the anomalously low pKa measured for the compound. A similar explanation would also account for a trans conformer being found in the crystal structures of the bromide salts of butaclamol and dexaclamol.

Antipsychotic Agents↗

PubMed1977

Effect of butaclamol, a new neuroleptic, on serotoninergic mechanisms.

Butaclamol (1.0-0.1 mg kg-1, i.p.) and spiroperidol (1-0-0-5 mg kg-1, i.p.) but not (-)-butaclamol (15 mg kg-1, i.p.), blocked the hyperactivity induced in rats by tranylcypromine-L-tryptophan pretreatment. Neither butaclamol nor spiroperidol altered the accumulation of brain 5-HT following parglyine or the decline of brain 5-HT following inhibition with the tryptophan hydroxylase inhibitor alpha-propyldopacetamide thus indicating that butaclamol and spiroperidol do not affect either the synthesis or the turnover of brain 5-HT. It is concluded that the antagonism of the tranylcypromise-L-tryptophan-induced hyperactivity by butaclamol and spiroperidol is due to their blockade of dopaminergic receptors rather than an action on neuronal serotoninergic mechanisms.

Animals↗

PubMed1976

Effect of structural analogs of butaclamol (a new antipsychotic drug) on striatal homovanillic acid and adenyl cyclase of olfactory tubercle in rats.

The 3-isopropyl (I), 3-cyclohexyl (II) and 3-phenyl (III) analogs of the new antipsychotic drug butaclamol, which contains a 3-tertiary butyl group, and their respective (+)-enantiomers, but not (-)-enantiomers, caused a dose related elevation of rat striatal homovanillic acid concentration, indicative of an increased dopamine (DA) turnover; droperidol also exhibited this activity. The order of activity of the (+)-enantiomers was (butaclamol) approximately II greater than I greater than III. A decrease in striatal DA was observed with (+)-I and (+)-III at the highest dose used, but not at one-half the dose. Each analog antagonized the DA-induced increase in adenyl cyclase (EC 4.6.1.1) activity of olfactory tubercle homogenates, the order of activity of the racemates (except for II) AND (+)-ENANTIOMERS BEING (BUTACLAMOL) APPROXIMATELY I greater than III greater than II. The (+)-enantiomers of butaclamol and analogs were two to four times more potent than their respective racemates, with (+)-butaclamol and (+)-I displaying activity generally equivalent to fluphenazine. The respective (-)-enantiomers were ineffective indicating a stereochemical specificity for DA-receptor blockade. Such analogs presented should be of value in elucidating dopaminergic mechansims.

Adenylyl Cyclases↗

PubMed1977

Effect of flupenthixol and butaclamol isomers on prolactin secretion in rats.

Cis (alpha)-flupenthixol and (+)-butaclamol are effective anti-psychotic agents but trans (beta)-flupenthixol and (-)-butaclamol are not. alpha-Flupenthixol was found to be 245 times more active in elevating rat plasma prolactin than the beta-isomer. The discrepancy between (+)-butaclamol and (-)-butaclamol was even greater. These results support the hypothesis that the dopamine receptors that mediate the effects of dopamine on prolactin secretion are similar to those that mediate the anti-psychotic effect of neuroleptic drugs.

Animals↗

PubMed1976

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

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.

Animals↗

PubMed1975

The effect of butaclamol and of other neuroleptic agents on the apomorphine-elicited inhibition of synaptosomal tyrosine hydroxylase activity.

The effects of the two enantiomers of butaclamol and of several neuroleptics on the apomorphine-elicited inhibition of synaptosomal tyrosine hydroxylase activity was investigated. The (+) but not the (-) enantiomer of butaclamol reverses the apomorphine-elicited enzyme inhibition. (+) Butaclamol is more potent than the other tested neuroleptics. All the tested neuroleptics reverse the apomorphine-elicited enzyme inhibition but their relative potency differs. Using two criteria, namely the concentrations of neuroleptics required to reverse enzyme inhibition maximally or by 25%, the order of decreasing potency is as follows: (+) butaclamol, fluphenazine, haloperidol, pimozide, chlorpromazine. The results suggest that the reversal of apomorphine-elicited inhibition of synaptosomal tyrosine hydroxylase activity is a valid test model for screening antipsychotic drugs.

Animals↗

PubMed2004

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

An enantioseparation of the antipsychotic drug butaclamol in human plasma by high-performance liquid chromatography (HPLC) with solid phase extraction is presented. The separation was achieved on the vancomycin macrocyclic antibiotic chiral stationary phase (CSP) Chirobiotic V with a polar ionic mobile phase (PIM) consisting of methanol : glacial acetic acid : triethylamine (100:0.2:0.05, v/v/v) at a flow rate of 0.5 ml/min. The detection wavelength was 262 nm. Bond Elut C18 solid phase extraction cartridges were used in the sample preparation of butaclamol samples from plasma. The method was validated over the range of 100-3,000 ng/ml for each enantiomer concentration (R(2) > 0.999). Recoveries for (+)- and (-)-butaclamol were in the range of 94-104% at the 300-2,500 ng/ml level. The method proved to be precise (within-run precision ranged from 1.1-2.6% and between-run precision ranged from 1.9-3.2%) and accurate (within-run accuracies ranged from 1.5-5.8% and between-run accuracies ranged from 2.7-7.7%). The limit of quantitation (LOQ) and limit of detection (LOD) for each enantiomer in human plasma were 100 ng/ml and 50 ng/ml, respectively.

Anti-Bacterial Agents↗

PubMed1985

Dopaminergic activity of four analogs of butaclamol.

The displacing potency of four analogs of the neuroleptic drug butaclamol were evaluated using dog striatal tissue and [3H]-Spiroperidol as ligand. Although significantly less powerful than the parent compound, two of them (N-isobutyl butaclamol equatorial; N-methyl butaclamol equatorial) could be used for dopaminergic receptor studies.

Animals↗

PubMed1979

Use of the butaclamol template in a search for antipsychotic agents with lessened side effects.

A number of molecular similarities between the antipsychotic agents butaclamol and clozapine were noted. Based on the premise that this was a strong indicator of a common mechanism of action (i.e., binding at the antagonist state of the dopamine receptor), a research approach was described. Three simplified analogues (4,8, and 12a) of butaclamol which still retained the molecular functionalities of the parent structure were synthesized and tested in the haloperidol receptor assay. 1-(5-Methyl-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene)-4-tert-butyl-4-piperidine (12a) displaced tritiated haloperidol with an IC50 value of 2.4 nM, as compared to a value of 0.5 nM for butaclamol However, when 12a was tested in vivo or in the spiroperidol receptor assay it was found to be considerably less potent.

Animals↗

PubMed1978

Neuroleptics related to butaclamol. An investigation of the effects of chlorine substituents on the aromatic rings.

The synthesis of analogues of the antipsychotic drug butaclamol bearing chloro substituents on the benzene rings is described. On the basis of a perceived topographical similarity of a putative chlorophenylethylamine pharmacophore present in these analogues and in VUFB-10032 and doclothepin, agents related to octoclothepin which do not induce catalepsy, they have been tested for "noncataleptic" neuroleptic activity. None of the butaclamol analogues exhibit this type of activity. Depending on the position of the chlorine, the analogues either retained butaclamol-like activity or were inactive.

Animals↗

PubMedDate not supplied

Stereospecific antagonism by d-butaclamol of dopamine-induced relaxation of the isolated rabbit mesenteric artery.

We characterized the properties of vascular dopamine receptors on isolated rabbit mesenteric arteries preincubated with phenoxybenzamine (10(-5) M) and contracted with prostaglandin F2 alpha (PGF2 alpha). The dose-response curve for dopamine-induced relaxation was shifted to the right by the dopamine receptor antagonist d-butaclamol (10(-7)--3 X 10(-6) M) in a concentration-dependent manner. The pA2 value for d-butaclamol was calculated as 6.77. In contrast, even a very high concentration (3 X 10(-6) M) of l-butaclamol had no effect, indicating that vascular dopamine receptors require stereospecificity of antagonists. In the same preparation the mechanism of relaxation by 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN; 3 X 10(-7)--10(-4) M) and bromocriptine (10(-6)--3 X 10(-4) M) was found to be dopaminomimetic, since only the dopamine receptor antagonists droperidol (10(-5) M) and metoclopramide (5 X 10(-5) M) could inhibit relaxations, whereas the beta-adrenoceptor antagonists pindolol (10(-7) M) and propranolol (10(-6) M) were without effect. It is concluded that receptors specific for dopamine exist on the rabbit mesenteric artery, which may tentatively be classified as belonging to the D1-type.

Animals↗

PubMed1978

Butaclamol in the treatment of schizophrenia. A standard-controlled clinical trial.

A 16-week, standard-controlled, double-blind study was conducted to compare the efficacy of butaclamol with that of fluphenazine in the treatment of 24 newly admitted schizophrenic patients. Statistically significant improvement occurred in the entire population in the total scores of the BPRS and PAS; in the activation, anergia, thought disturbance and hostile/suspiciousness factor scores of the BPRS; and in the scores of 9 of the 12 factors of the PAS. There were no statistically significant differences between the scores of the two treatment groups on the total or factor scores of either scale during the course of the clinical trial. The most frequently occurring adverse effects in the butaclamol group were rigidity, akathisia and excitement/agitation. The most frequently occurring adverse effects in the fluphenazine group were insomnia, decreased motor activity and tremor. It is concluded that butaclamol exerts potent neuroleptic effects on schizophrenic patients.

Adult↗

PubMed1988

The effect of the stereoisomers of butaclamol on neurotensin content in discrete regions of the rat brain.

The prevailing hypothesis concerning the mechanism of antipsychotic drug action is principally based on the striking correlation between their clinical potency and their potency in blockade of D2 dopamine receptors. However, most of these compounds also have effects at serotonin, acetylcholine, histamine, and alpha-adrenergic receptors and have recently been shown to alter the concentrations of certain neuropeptides in the rat brain after chronic drug administration. One such neuropeptide that is increased in concentration in dopamine terminal regions by clinically effective neuroleptic drugs is neurotensin (NT). Neurotensin is closely associated with dopamine neurons, as demonstrated by evidence derived from anatomic, physiologic, and pharmacologic studies. In this report, we determined the effects of chronic administration of the potent D2 receptor antagonist (+)-butaclamol and its inactive (-) stereoisomer on regional brain NT content. Moreover, we sought to determine whether the effects of haloperidol on NT concentrations can be antagonized by concomitant administration of an indirect dopamine agonist, d-amphetamine. Neurotensin content in the caudate nucleus and nucleus accumbens of the rat were significantly increased by 3 weeks of daily injections of haloperidol or (+)-butaclamol, but not (-)-butaclamol. d-Amphetamine did not alter this effect of haloperidol on NT concentrations in either the nucleus accumbens or caudate nucleus. These data are concordant with the hypothesis that D2 receptor blockade is required for NT concentration increases after antipsychotic drug treatment and that the increase in synaptic cleft dopamine content produced by d-amphetamine cannot reverse this effect of dopamine receptor antagonists.

Animals↗

PubMed1978

Histamine-, norepinephrine-, and dopamine-sensitive central adenylate cyclases: effects of chlorpromazine derivatives and butaclamol.

A series of recently available derivatives (quaternary and hydroxylated) of chlorpromazine (CPZ) and butaclamol were evaluated with respect to antagonism of norepinephrine- (NE) (rat cerebral cortex), dopamine- (DA) (rat striatum) and histamine- (H) sensitive (rabbit cerebral cortex) adenylate cyclases. With incubated tissue slices (rat and rabbit cortices) CPZ-CH3, 7-OH-CPZ-CH3, beta-OH-CPZ and butaclamol displayed a capacity to inhibit either NE- or H- induced accumulation of adenosine cyclic 3',5'-monophosphate (cAMP). With the broken cellular enzyme responsive to DA, rather potent inhibition of enzyme activity (IC50 less than 24 micron) occurred with butaclamol, beta-OH-CPZ, 7,8,beta-triOH-CPZ, 7,8-dioxo-beta-OH-CPZ and 3,7,8-triOH-CPZ. It is concluded that the metabolites of CPZ contribute to the central therapeutic and/or side effects of the parent compound.

Adenylyl Cyclases↗

PubMedDate not supplied

Evaluation of butaclamol in chronic schizophrenic patients.

In a double-blind, placebo-controlled study, an attempt was made to evaluate butaclamol in chronic schizophrenic patients using chlorpromazine (CPZ) as the standard comparative drug. With doses up to 50 mg/day, butaclamol was shown to have significant antipsychotic activity comparable to CPZ but with a much higher incidence of extrapyramidal signs. A more reasonable maintenance dose may be in the range of 5 to 20 mg/day. Rebound insomnia was noted again with butaclamol, which warrants further study.

Adult↗

PubMed1991

NMR studies of the conformational interconversion of butaclamol in solution.

1H NMR experiments at 300 MHz have been carried out to determine the identity and study the interconversion of two conformations of butaclamol in solution. The hydrochloride salt in DMSO exists as an equilibrium mixture of two conformations, which differ in their stereochemistry about the ring junction that contains the single nitrogen atom in butaclamol. The trans form has a relative population of 80% and the cis I form 20%. In CDCl3 only the trans form is observed, while in CDCl3-DMSO mixtures, both forms are detected in a ratio (trans:cis I) that decreases as the percentage of CDCl3 decreases. For the free base in either CD2Cl2 or DMSO, only a single set of resonances is observed at room temperature, but as temperature is lowered, peaks from methine protons H4a and H13b near the ring junction broaden and (for samples in CD2Cl2) eventually split into two resonances corresponding to the cis and trans forms. It is suggested that nitrogen inversion is the dynamic process responsible for the interconversion of the two forms. Line shape analysis as a function of temperature yielded an energy barrier of 9.6 +/- 0.5 kcal/mol for the interconversion, in good agreement with values obtained from saturation transfer experiments. In the hydrochloride salt, the barrier in DMSO was somewhat higher, i.e., 17.3 +/- 0.9 kcal/mol, as determined by saturation transfer and variable-temperature measurements.

Butaclamol↗