Quipazine-induced Head Twitches Research Articles

Design, synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl]phenyl}thiazoles as atypical antipsychotic agents

A series of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl] phenyl} thiazoles were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were designed, synthesized, and characterized by spectral data (IR, 1H NMR, and MS) and the purity was ascertained by microanalysis. The D2 and 5-HT2A affinity of the synthesized compounds was screened in vitro by radioligand displacement assays on membrane homogenates isolated from rat striatum and rat cortex, respectively. Furthermore, all the synthesized final compounds (10a–g; 11a–g; 12a–g) were screened for their in vivo pharmacological activity in Swiss albino mice. D2 antagonism studies were performed using climbing mouse assay model and 5-HT2A antagonism studies were performed using quipazine-induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy and 12d, 11f, and 10a were found to be the most active compounds with 5-HT2A/D2 ratio of 1.23077, 1.14286, and 1.12857, respectively, while the standard drug risperidone exhibited 5-HT2A/D2 ratio of 1.0989. Among the twenty one new chemical entities, three compounds (12d, 11f, and 10a) were found to exhibit better atypical antipsychotic activity as they were found to have higher Meltzer index than the standard drug risperidone.

Design, synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 2-{4-[4-(2,5-disubstituted thiazol-4-yl)phenylethyl]piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles as atypical antipsychotic agents

A series of 2-{4-[4-(2,5-disubstituted thiazolyl)phenylethyl] piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized either by microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, 1H NMR, and MS) and the purity was ascertained by microanalysis. The D2 and 5-HT2A affinity of the synthesized compounds was screened in vitro by radioligand displacement assays on membrane homogenates isolated from rat striatum and rat cortex, respectively. Furthermore, all the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. The D2 antagonism studies were performed using climbing mouse assay model and 5-HT2A antagonism studies were performed using quipazine-induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy and 10f is the most active among the synthesized compounds with 5-HT2A/D2 ratio of 1.1286 although the standard drug risperidone exhibited 5-HT2A/D2 ratio of 1.0989.

A novel 5-HT 2A receptor antagonist exhibits antidepressant-like effects in a battery of rodent behavioural assays: Approaching early-onset antidepressants

Collective evidence suggests that inhibition of neuronal 5-hydroxytryptamine type 2A (5-HT 2A) receptors contributes to the assuagement of depression-like behaviour in rodents. The present study evaluated the antidepressant-like effect of the 5-((4-benzo [α] isothiazol-3-yl) piperazin-1-yl) methyl)-6-chloroindolin-2-one (BIP-1), a compound having affinity to 5-HT 2A receptors, using a rodent behavioural test battery. Acute BIP-1 (0.25–4 mg/kg) pretreatment reduced the quipazine-induced head twitches in mice and produced antidepressant-like effects in mouse forced swim and tail suspension tests. BIP-1 reversed the depressogenic-like effects of meta-chlorophenyl piperazine and augmented the antidepressant-like effects of amitryptiline and harmane. Chronic (14 days) treatment with BIP-1 (1 and 2 mg/kg) or amitriptyline (10 mg/kg) alleviated the behavioural anomalies of olfactory bulbectomised rats in modified open field exploration, social interaction, hyperemotionality and sucrose preference paradigms. When BIP-1 treatment was combined with amitryptyline, a short duration regimen (7 days) was sufficient to reverse the bulbectomy induced anomalies. This investigation revealed that 5-HT 2A receptor antagonism is the principal mechanism behind the antidepressant-like effects of BIP-1. Finally, we propound the combination of 5-HT 2A receptor antagonists and tricyclic antidepressants as a likely strategy to achieve an early-onset of antidepressant action.

Synthesis and preliminary screening of novel N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides as potential atypical antipsychotic agents

A series of N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides were synthesized as prospective novel atypical antipsychotic agents. Microwave irradiation of acetyl glycine (I) with substituted piperazines in the presence of DCC in DMF for about 3-5 min gave the titled compounds (P:1-7). All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D2 antagonism studies were performed using the climbing mouse assay model and 5-HT2A antagonism studies were performed using quipazine induced head twitches in mice. Among the synthesized compounds P4 was found to be the most active compound.

Synthesis and preliminary pharmacological evaluation of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides as novel atypical antipsychotic agents

A series of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized by either microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, 1H NMR, and MS) and the purity was ascertained by microanalysis. All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D2 antagonism studies were performed using climbing mouse assay model and 5-HT2A antagonism studies were performed using quipazine induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy. AG 3 was found to be the most active compound.

In-vivo assessment of 5-HT2A and 5-HT2C antagonistic properties of newer antipsychotics.

The effects of serotonin (5-HT) receptor ligands on the MK 212 (6-chloro-2[1-piperazinyl]pyrazine) discriminative stimulus and quipazine-induced head twitches were studied in rats. 5-HT1A (8-OH-DPAT) and preferential 5-HT2A (DOI) receptor agonists did not generalize to the discriminative stimulus. The 5-HT2B/2C-receptor antagonist, SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole), and the 5-HT2A/2C-receptor antagonist, ritanserin, acted as potent antagonists, whereas the 5-HT2A-receptor antagonist, MDL 100.151 ([(+/-)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4- piperidine-methanol), produced minor and inconsistent inhibition. SB 206553 was a weak antagonist against quipazine-induced head twitches, whereas MDL 100.151 and ritanserin were potent antagonists. This suggests that the MK 212 discriminative stimulus is mediated by 5-HT2C receptors, while quipazine-induced head twitches are mediated primarily by 5-HT2A receptors. The effects on quipazine-induced head twitches were comparable to previously published effects on the DOI discriminative stimulus. 5-HT2A- and 5-HT2C-receptor antagonistic potencies of clozapine, olanzapine, risperidone, sertindole and ziprasidone were compared in the same models. Clozapine showed similar potencies in both models, while sertindole, olanzapine and risperidone inhibited quipazine-induced effects more potently than the MK 212 discriminative stimulus. Ziprasidone exerted a minor preference for 5-HT2A- compared to 5-HT2C-receptor-mediated effects. The ratio between in vivo inhibitory potencies at 5-HT2A and 5-HT2C receptors did not correlate with corresponding ratios from in-vitro affinity and ex-vivo occupancy studies in the literature.

Brain-to-blood partition and in vivo inhibition of 5-hydroxytryptamine reuptake and quipazine-mediated behaviour of nefazodone and its main active metabolites in rodents.

The brain/plasma partition of nefazodone, hydroxynefazodone (OHNFZ) and m-chlorophenyl-piperazine (mCPP) and their antagonism of p-chloroamphetamine (PCA)-induced 5-hydroxytryptamine (5-HT) depletion and quipazine-induced head twitches were compared in rodents. Nefazodone (30 mg kg(-1), i.p.) rapidly entered the brain but concentrations were exceeded by mCPP, the metabolic ratio being 47 and 10 in the mouse and rat respectively. OHNFZ was detectable in plasma but never in brain. Brain concentrations of OHNFZ in the mouse (30 mg kg(-1), i.p.) were less than 10% of those in plasma, confirming a poor blood-brain barrier penetration. Concentrations of its metabolite mCPP were similar to those after 5 mg kg(-1)(i.p.) mCPP. In the mouse, nefazodone (30 mg kg(-1)) antagonized the 5-HT depleting effect of PCA 2 h after dosing, when it had disappeared from brain but when mCPP concentrations were similar to those after 5 mg kg(-1) (i.p.) mCPP. However, mCPP antagonized PCA less than nefazodone. In the rat, nefazodone pretreatment (30 mg kg(-1), 15 min) prevented (97% of inhibition) quipazine-induced head twitches. The effect was weaker (65% of inhibition) but significant when only mCPP was detected in brain. Analysis of brain concentrations of the two compounds after their ED50 against quipazine indicated that both contributed to the effect, although nefazodone was more active than mCPP in terms of concentrations required to obtain a comparable reduction of twitches. These findings show that mCPP concentrates in the brain following injection of nefazodone and may play a role in preventing quipazine-induced behaviour and PCA-induced 5-HT depletion. In contrast OHNFZ poorly enters the brain and its in vivo activity is mostly due to its biotransformation to mCPP.

Noncataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles.

A series of 1-(4-fluorophenyl)-1H-indoles substituted at the 3-position with 1-piperazinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperidinyl was synthesized. Within all three subseries potent dopamine D-2 and serotonin 5-HT2 receptor affinity was found in ligand binding studies. Quipazine-induced head twitches in rats were inhibited by most derivatives as a measure of central 5-HT2 receptor antagonism. Piperazinyl and tetrahydropyridyl indoles were cataleptogenic, while piperidyl substituted indoles surprisingly were found to be noncataleptogenic or only weakly cataleptogenic. Noncataleptogenic piperidyl derivatives also failed to block dopaminergic-mediated stereotypies, that is methyl phenidate-induced gnawing behavior in mice. These profiles resemble that of the atypical neuroleptic clozapine. 1-Ethyl-2-imidazolidinone was found to be the optimal substituent of the basic nitrogen atom in order to avoid catalepsy. The atypical neuroleptic 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl] ethyl]-2-imidazolidinone (sertindole, compound 14c) was selected for further development as a result of these structure/activity studies.

Serotonin receptor blocking effect of SCH 23390

The effect of SCH 23390 administration on the serotonin system-dependent head twitch behavior was studied in the rat. A small dose of SCH 23390 (1.25 μg/kg), injected 20 min before the test, decreased the number of quipazine-induced head twitches. Repeated treatment with SCH 23390 (0.5 mg/kg, SC), once a day for 18 days, increased the number of spontaneously occurring and quipazine-induced head twitches. The enhancing effect of repeated administration of SCH 23390 was blocked by cyproheptadine (0.4 mg/kg). The results indicate that acure injection of SCH 23390 blocks central serotonin receptors, whereas repeated treatment induces their functional supersensitivity.

REM sleep deprivation changes behavioral response to catecholaminergic and serotonergic receptor activation in rats

The effects of REM sleep deprivation (REMD) on apomorphine-induced aggressiveness and quipazine-induced head twitches in rats were determined. Forty-eight hr of REMD increased apomorphine-induced aggressiveness, and reduced (immediately after completing of REMD) or increased (96 hr after completing of REMD) quipazine-induced head twitches. Results are discussed in terms of similarity to pharmacological effects of other antidepressive treatments.

Citalopram: a new potent inhibitor of serotonin (5-HT) uptake with central 5-HT-mimetic properties.

Citalopram (1--16 mg/kg), but not amitriptyline, clomipramine, imipramine or zimelidine, stimulated the hind limb flexor reflex in the spinal rat. This stimulatory effect was abolished by serotonin (5-HT) receptor blocking agents (cyproheptadine, metergoline) and prevented ty p-chlorophenylalanine, an inhibitor of 5-HT synthesis. Citalopram (20 mg/kg), similarly but more strongly than clomipramine (20 mg/kg), prevented both fenfluramine- and p-chloroamphetamine-induced hyperthermia in rats kept at 28 degrees C. In contrast to amitriptyline and imipramine, citalopram did not reduce the number of quipazine-induced head twitches in rats (ID50 greater than 50 mg/kg). Also, unlike the above mentioned antidepressants, it did not antagonize, but rather potentiated the 5-HT-mediated rise in blood pressure in pithed rats. The results obtained indicate that, unlike the presently known inhibitors of 5-HT uptake, citalopram considerably potentiates serotonergic transmission, possibly by producing very strong inhibition of uptake without simultaneous blockade of the postsynaptic 5-HT receptors.

Is Ro 11-2465 (cyan-imipramine) an antagonist of postsynaptic serotonin receptors?

Ro 11-2465, a selective inhibitor of serotonin uptake of the imipramine group, was examined for its central and peripheral antiserotonin activity. Ro 11-2465 (10 mg/kg) antagonized the stimulation of the hind limb flexor reflex in the spinal rat evoked by serotonin agonists of direct mode of action (LSD, quipazine, m-chlorophenylpiperazine). However, in doses up to 20 mg/kg it did not inhibit the clonidine-induced stimulation of the flexor reflex. It also reduced the number of the quipazine-induced head twitches in rats (ID50 = 20.1 mg/kg) and, in doses 0.3--10.0 mg/kg, dose-dependently attenuated the pressor response to serotonin in the pithed rat. Like doxepine, amitriptyline, clomipramine and imipramine, Ro 11-2465 reduced the serotonin-induced contractions of the rat stomach fundus strip (its IC50 = 5 x 10(-5) M). The obtained results indicate that like other tricyclic inhibitors of serotonin uptake, Ro 11-2465 may also weakly block the postsynaptic serotonin receptors. Additional studies with fluoxetine and Org 6582 indicate that anti-serotonin properties of tricyclic compounds are not related to the serotonin uptake blocking properties.

Inhibition of “wet shakes” during morphine abstinence by an antagonist of opiate analgesia

An antagonist of morphine analgesia, N-cyclopropylmethylnorazidomorphine (CAM) inhibited the “wet shakes” appearing during spontaneous or nalorphine-precipitated morphine abstinence. CAM inhibited the pinna reflex more strongly than did morphine and selectively antagonized quipazine-induced head twitches; its inhibition of head twitches induced by 5-hydroxytryptophan or LSD seemed unspecific. The results suggest that the opiate receptors involved in the inhibition of some symptoms of morphine abstinence and of the pinna reflex differ from those involved in opiate analgesia.