Neuroleptic Compounds Research Articles

Neuroleptic-induced reduction of quipazine-elicited head-twitches in rats: Possible involvement of striatal dopaminergic supersensitivity

Rats were treated with a single large dose of various neuroleptic compounds and 5–7 days after, they were assayed for either behavioral sensitivity to apomorphine (hypermotility and stereotyped behavior) or head-twitch response to the mixed serotonin-dopamine agonist quipazine. The animals withdrawn from chlorpromazine, fluphenazine, haloperidol, metoclopramide and the D1 selective blocker SCH 23390, showed enhanced hypermotility and/or stereotyped responses to apomorphine and reduced head-twitch response to quipazine. The rats withdrawn from thioridazine, (-)-sulpiride and sultopride responded to apomorphine only with enhanced hypermotility while their response to quipazine was either unchanged or even increased. The results are discussed in terms of dopaminergic brain areas and/or receptor subtypes involved in the modulation of the head-twitch response to quipazine. We conclude that an enhancement of dopaminergic tone at the striatal level could be related to the reduced head-twitch response to quipazine.

Desenkephalin-γ-endorphin and neuroleptics counteract the DP-7-ATN-induced hypomotility after intra-accumbens treatment

Injection of the selective presynaptic dopamine agonist N,N-dipropyl-7-hydroxy-2-aminotetralin (DP-7-ATN, 1 fg to 1 μg) into the nucleus accumbens decreased motor activity. The reduction of motor activity was reversed by pretreatment with haloperidol (10 pg), (−)-sulpiride (10 pg) or desenkephalin-γ-endorphin (DEγE) (100 pg). These results support the hypothesis that DEγE may interfere with presynaptically located D-2 dopamine receptor systems in the nucleus accumbens. Furthermore, the use of DP-7-ATN in the described test procedure might be a useful model for testing novel neuroleptic compounds in vivo.

Commentary on Dinan's hypothesis.

Dinan's paper seeks to question the validity of the now widely accepted hypothesis that neuroleptic drugs of various different chemical categories all act by a common mechanism, namely by blockade of dopamine receptors of the D2 type in brain (for review see Creese et al, 1978, 1983; Iversen, 1985). While it is always refreshing to re-examine existing scientific dogma, his criticisms did not appear to me to be very substantial. Having quite fairly reviewed the evidence in favour of the “dopamine hypothesis” for neuroleptic drug action, Dinan summarises his reasons for questioning it. He points out that many neuroleptic drugs have potent actions on a number of other targets, apart from the dopamine receptors in brain. This is indeed so, and the archetypal compound, chlorpromazine, has a particularly rich spectrum of pharmacological activity, being a potent antagonist of serotonin (5-HT2) receptors, ?-adrenoceptors, and histamine (HI) receptors in brain and other tissues. Other neuroleptics also have potent actions on a number of other systems. Indeed, if one were to have studied only chlorpromazine, it is doubtful whether the “dopamine hypothesis” could ever have been developed. The strength of this hypothesis lies in the fact that of all the diverse pharmacological actions which different neuroleptic drugs exhibit, this is the only action that is common to all neuroleptic compounds. Furthermore, in a large group of neuroleptics, which differ widely in potency (doses in man ranging from 1 mg/day to almost 1000 mg/day), the potencies of these drugs as dopamine (D2) antagonists correlate significantly with their clinical potencies. Attempts to make such correlations with any other known pharmacological properties of these drugs fail to show significance (Creese et al, 1978, 1983).

Drug design: Le contrôle LUMO du pharmacophore neuroleptique

The aromatic ring of the antagonist of the dopaminergic receptor behaves as an electron acceptor within its interactions with the receptor. The energy of the lower unoccupied molecular orbital ( ϵ LUMO ) is correlated with the biological activity for different series of neuroleptic compounds. The principle of interaction LUMO antagonist—HOMO receptor (Principle La—Hr), presented previously for the phenothiazine series, is extended to various series of antagonists of the dopaminergic receptor: thioxanthenes, butyrophenones, benzisoxazoles and benzamides. The Principle La—Hr is refined on a model series of 16 phenothiazines by a multilinear regression giving the biological activity versus 3 variables, with a stepwise procedure. The variable ϵ LUMO has the strongest contribution, the aliphatic amine chain has a moderate contribution and the variation of lipophilicity induced by the substituent of the aromatic ring in position 2 has only a very weak contribution. The correlation is used to predict, with success, the relative activity of two new phenothiazines: mesoridazine and thioridazine.

Results of an open phase II study with zotepine--a new neuroleptic compound.

Zotepine is a new tricyclic neuroleptic with a pharmacological profile comparable to substances such as thioridazine and chlorpromazine. Ten patients fulfilling DSM-III criteria of paranoid schizophrenia were included in an open pilot study at the Department of Psychiatry in Innsbruck. Neuroleptic efficacy, optimal dose, side effects, and the influence on serum prolactin levels were evaluated. Definite onset of antipsychotic action could be demonstrated between days 5-10, and approximately 400 mg/die seems to be an optimal dose. Four patients showed side effects of a minor degree that had no influence on the course of therapy. These results suggest that Zotepine is a rapidly acting neuroleptic with a high benefit-risk ratio. Further double-blind studies will be needed to reinforce these preliminary data.

Pharmacological evaluation of HP 370, a potential atypical antipsychotic agent: 2. In vitro profile

AbstractHP 370, 4,9‐dibromo‐6‐(4‐methyl‐1‐piperazinyl)benzo[b]pyrrolo[3,2,1‐jk][1,4] benzodiazepine, a compound that has an atypical antipsychotic profile in vivo, was tested for activity in a number of neurotransmitter receptor binding and uptake assays and compared with serveral typical and atypical antipsychotic compounds. The in vitro profile of HP 370 was most similar to that of clozapine, with the notable exception that HP 370 was inactive as an inhibitor of quinuclidinyl benzilate (QNB) binding (IC50 10−5). HP 370, like clozapine, was a relatively weak and nonselective inhibitor of dopamine (DA) receptor subtypes, whereas sulpiride, another compound reported to be atypical, is a very selective but weak inhibitor of dopamine‐2(D2) receptors. HP 370 and clozapine inhihited WB4101 binding with high affinity, indicating α1‐adrenergic receptor blockade. Neither HP 370 nor the standard neuroleptic compounds inhibited flunitrazepam or gamma‐aminobutyric acid (GABA) binding. HP 370, Clozapine, and sulpiride were inactive as inhibitors of norepinephrine (NE), DA, and 5HT uptake, whereas HP 370 AND clozapine were weark inhibitors of GABA uptake. Based on this in vitro data, the mesolimbic site‐selectivity of HP 370 seen in vivo cannot be explained by anticholinergic GABA‐mimetic activity in the DA‐parative results point to a distinct advantage of an atypical neuroleptic, without the antocholinergic side effects of clozapine.

Analysis of the pharmacological properties of clozapine analogues using molecular electrostatic potential surfaces

Molecular electrostatic potential surfaces have been used to study a series of neuroleptic compounds, clozapine and clozapine analogues, with similar structures but two rather different pharmacological profiles. Using the electrostatic potential surfaces, the compounds studied could be assigned to one of two distinct categories corresponding to the two pharmacological classes. The results of this study suggest that the molecular electrostatic potential surfaces may be useful in the a priori prediction of pharmacological properties of untested clozapine analogues.

The benzazepine SCH 23390 increases plasma levels of cortisol in the conscious dog

The effect of neuroleptics on the hypothalamopituitary-adrenal system has been early recognized, but never adequately related to antipsychotic or side effects produced by dopamine antagonists. We are now presenting results showing that the newly characterized dopamine D-1 receptor antagonist, SCH 23390 (0.1 mg/kg i.v.) as well as the mainly dopamine D-2 receptor antagonists, haloperidol (0.1 mg/kg i.v.) and chlorpromazine (1 mg/kg i.v.), produced an increase of cortisol levels (108, 144 and 226% respectively, 20 min after the injection) determined by radioimmunoassay in blood samples collected from superficial veins of the legs of conscious dogs. The 5-HT2 receptor antagonist, cyproheptadine (0.2 mg/kg i.v.), did not modify the cortisol levels. These results suggest that cortisol increase is an effect common to neuroleptic compounds, independently of their relative antagonistic action at dopamine D-1 or D-2 receptors.

Interactions of neuroleptic compounds at α2-adrenergic receptor affinity states in bovine caudate nucleus

Several recent studies have suggested a connection between neuroleptics and/or dopamine systems, and α 2-adrenergic receptors. Competition of a variety of neuroleptics at specific α 2-adrenergic binding sites (labeled with [ 3H]rauwolscine or [ 3H]p-aminoclonidine) in bovine caudate and cortex was examined. Few of the compounds were potent competitors, with (+)-butaclamol, α-flupenthixol, clozapine and pimozide the most potent (IC 50 range 100–600 nM), while trifluopromazine, mesoridazine, and haloperidol were the least potent (IC 50 range 5 000– 10 000 nM). These findings indicate that few, if any, of the examined neuroleptics have specific, high-affinity interactions with the multiple affinity states of the α 2-adrenergic receptor.

Neuroleptic activity and dopamine-uptake inhibition in 1-piperazino-3-phenylindans.

A series of 1-piperazino-3-phenylindans was synthesized and tested for neuroleptic and thymoleptic activity. Neuroleptic activity was found only in trans racemates and was associated with one of the enantiomers only. The potent and long-acting neuroleptic compound trans-4-[3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-yl]-1-piperazineethanol (Lu 18-012, tefludazine) was developed by systematic variation of structural components. Thymoleptic activity was optimized, especially with respect to dopamine-uptake inhibition. No geometrical stereoselectivity was found with regard to dopamine-uptake inhibition, but a high enantioselectivity could be demonstrated for both cis and trans racemates. The most potent compounds were 1-piperazino-3-(3,4-dichlorophenyl)indans with IC50 values of about 2nM for inhibition of dopamine uptake.

Potent lipophilic substituted benzamide drugs are not selective D-1 dopamine receptor antagonists in the rat

The substituted benzamide drugs YM 09151-2 and clebopride potently inhibited apomorphine-induced stereotyped behaviour in the rat and caused displacement of the specific binding of [3H]spiperone to D-2 binding sites on striatal membranes in low nanomolar concentrations. Other substituted benzamide drugs including metoclopramide, sultopride and flubepride also inhibited stereotyped behaviour to a greater or lesser degree, but were less potent in displacing [3H]spiperone from D-2 sites. YM 09151-2 and clebopride only weakly displaced specific binding of [3H]piflutixol to D-1 sites on rat striatal membranes, and only weakly inhibited striatal dopamine stimulated adenylate cyclase activity, when compared with cis-flupenthixol. The other substituted benzamide drugs did not displace [3H]piflutixol or inhibit dopamine stimulation of adenylate cyclase activity in the concentration range used. Clebopride and YM 09151-2 were highly lipophilic with apparent partition coefficient (log P') values equivalent to those of classical neuroleptic compounds, such as cis-flupenthixol. In contrast, the other substituted benzamide drugs were markedly less lipophilic. A log P' value of approximately 2 was required before inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding occurred. However, in excess of this value there was no correlation between either inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding and the lipophilicity of the various compounds. We conclude that potent lipophilic substituted benzamide drugs, like other members of the substituted benzamide series, are selective D-2 receptor antagonists. Inherent steric factors within the drug series would appear to dictate activity at D-1 and D-2 sites, although lipophilicity may contribute to actions in these environments.

Pharmacological specificity of conditioned avoidance response inhibition in rats: inhibition by neuroleptics and correlation to dopamine receptor blockade.

The inhibitory effect of 36 neuroleptic compounds on conditioned avoidance response (CAR) and unconditioned escape response (UER) has been studied in rats. All neuroleptics antagonized CAR in doses below those inhibiting UER and below those inducing catalepsy. Stereospecificity was shown in two cases. Significant correlation was found between CAR inhibitory and cataleptogenic potency. Also inhibition of amphetamine induced stereotypy, affinity to 3H-haloperidol binding sites in vitro and clinical potency was significantly correlated to CAR inhibition. CAR and UER inhibition induced by cis(Z)-flupentixol and haloperidol was attenuated by scopolamine, but was only weakly influenced by methysergide and prazosin. Among a wide range of other CNS active compounds tested, CAR was inhibited by alpha 1-adrenergic antagonists, benzodiazepines, a barbiturate, GABA agonists, morphine and a serotonin agonist, but in doses inducing other motor disturbances. It is concluded that CAR inhibition is a sensitive test for dopamine receptor antagonists. However, additional alpha-adrenergic activity found for some neuroleptics (e.g. clozapine, chlorprothixene) may contribute to the CAR inhibitory potency. Additional antimuscarinic activity of neuroleptics may moderately attenuate CAR inhibition whereas serotonin receptor blockade is of minor importance.

Plasticity of neostriatal dopamine receptors after nigrostriatal injury: Relationship to recovery of sensorimotor functions and behavioral supersensitivity

Rats given unilateral injections of 6-OHDA along the course of the mesotelencephalic dopaminergic projection show impairments in contralateral sensorimotor functions from which they often recover. Such rats also display an enhanced sensitivity to DA receptor stimulants, e.g. apomorphine, as revealed by contralateral turning, and an increased binding of neuroleptic compounds (e.g. [ 3H]spiroperidol) to the denervated striatum. This research examines the relationship of these receptor changes to both behavioral supersensitivity and recovery of sensorimotor functions by quantifying the time course of each phenomenon after injury. The supersensitivity to apomorphine and the behavioral recovery developed with a similar time course after injury, being evident within 1.5–3 days and reaching nearly maximal levels by 2 weeks postoperatively. A significant increase in in vivo [ 3H]spiroperidol binding to the denervated striatum occurred by 4 days postoperatively, and the magnitude of this change increased linearly during the first postoperative month. In contrast, the in vitro binding of this ligand to membranes of the denervated striatum was not increased until 3 weeks after the lesion. The results suggest that a proliferation of DA receptors may contribute to the pharmacological supersensitivity and the recovery of function, and that these early receptor changes may be revealed with greater sensitivity using in vivo binding techniques.

ChemInform Abstract: 4A,9B‐TRANS‐8‐FLUORO‐5‐(4‐FLUOROPHENYL)‐2‐(4‐(4‐FLUOROPHENYL)‐4‐HYDROXYBUTYL)‐2,3,4,4A,5,9B‐HEXAHYDRO‐1H‐PYRIDO(4,3‐B)INDOLE HYDROCHLORIDE, A NEW POTENT NEUROLEPTIC

AbstractMit überschüssigem Boran bildet die in acht Stufen aus p‐Fluorphenylhydrazin zugängliche Verbindung (I) den Komplex (II), dessen Zersetzung zu′(III) und dem entsprechenden Dehydratisierungsprodukt führt.

The use of thioproperazine, a phenothiazine derivative, as a ligand for neuroleptic receptors—I: In vitro studies

The use of [ 3H]thioproperazine (a neuroleptic of the phenothiazine family) as a ligand for neuroleptic receptors has been studied in vitro in various brain regions of the rat. Specific thioproperazine binding has been observed in two regions rich in dopamine terminals: striatum and nucleus accumbens. No specific binding was observed in frontal cortex and hippocampus. Thioproperazine binds with high affinity ( K d = 0.30 nM) to rat microsomal striatal fraction. In this fraction the number of binding sites (1.47 pmoles/mg protein) is rather similar to that found with haloperidol and spiperone, two neuroleptics of the butyrophenone type. Subcellular distribution of thioproperazine binding reveals a pattern similar to that of 5'-nucleotidase, a plasma membrane marker. This indicates that the receptor sites of [ 3H]thioproperazine are associated with membrane-like structures. Inhibition studies indicate that all neuroleptic compounds, belonging to different chemical families, are capable of displacing thioproperazine from its binding sites. The most potent drugs are spiperone, thioproperazine and pipotiazine. Dopamine and the two dopamine agonists, apomorphine and bromocryptine, present affinity for thioproperazine binding sites. It is concluded that thioproperazine, a phenothiazine neuroleptic, can be used, like the butyrophenone derivatives haloperidol and spiperone, as a ligand for studying neuroleptic receptors.

ChemInform Abstract: SYNTHESIS OF ISOMERIC THIENOBENZOTHIAZINES AND THEIR EFFECT ON DOPAMINE METABOLISM IN RAT BRAIN

The synthesis of the thieno[2,3-b]-, thieno[3,4-b]- and thieno[3,2-b]benzothiazines with a hydroxyethylpiperazinylpropyl side chain and various 2 substituents is described. The influence of these neuroleptic compounds on dopamine metabolism in vivo is quantitated by determining the rise in homovanillic acid concentrations in rat corpus striatum. Notable differences in activity were found among the isomers, which were useful for structure--activity correlations in the phenothiazine neuroleptics.

4a,9b-trans-8-Fluoro-5-(4-fluorophenyl)-2-[4-(4-fluorophenyl)-4-hydroxybutyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride, a new potent neuroleptic.

The preparation and testing of the two racemic diastereoisomers and the four optically active enantiomers of the title compound in in vitro and in vivo models for determining potential antipsychotic activity are described. Both racemic diastereoisomers and two of the four chiral enantiomers are potent and long-acting neuroleptic compounds.

Neuroleptic activity in 5-aryltetrahydro-gamma-carbolines.

A series of 5-aryltetrahydro-gamma-carbolines was prepared by a novel N-arylation procedure and tested for neuroleptic activity in a rat antiamphetamine model. The systematic exploration of structural parameters leading to 8-fluoro-5-(4-fluorophenyl)-2-[4-hydroxy-4-(4-fluorophenyl)butyl]-2,3,5-tetrahydro-1H-pyrido[4,3-b]indole (CP-36,584, flutroline), a potent and long-acting neuroleptic compound, is described. These semirigid compounds provide a new, structurally distinct series with which to probe the conformational requirements for potent activity at the dopamine receptor.

Synthesis of isomeric thienobenzothiazines and their effect on dopamine metabolism in rat brain.

The synthesis of the thieno[2,3-b]-, thieno[3,4-b]- and thieno[3,2-b]benzothiazines with a hydroxyethylpiperazinylpropyl side chain and various 2 substituents is described. The influence of these neuroleptic compounds on dopamine metabolism in vivo is quantitated by determining the rise in homovanillic acid concentrations in rat corpus striatum. Notable differences in activity were found among the isomers, which were useful for structure--activity correlations in the phenothiazine neuroleptics.

GABA-dopamine/neuroleptic interaction after systemic administration

In acute experiments GABA-agonists like muscimol and THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin 3-ol) potentiate stereotyped gnawing induced by DA-agonists like methylphenidate. In contrast neuroleptics are very potent antagonists against stereotypies. When combining a GABA-agonist with a neuroleptic compound the methylphenidate antagonistic effect of the latter is attenuated. The same attenuation of the antistereotypic effect of the neuroleptics is in some cases seen after additional treatment with benzodiazepines and anticholinergics. To investigate the influence of a GABA-agonist on the GABA-dopamine/neuroleptic interaction after repeated administration, THIP was given alone or in combination with haloperidol for twelve days. Repeated administration of THIP induces hypersensitive reactions to methylphenidate-induced gnawing but in contrast to the hyperactivity seen after repeated administration with neuroleptics the animals were calm and easy to handle. The supersensitivity induced by chronic neuroleptic treatment was not suppressed by additional treatment with THIP.