Ex vivo studies with iloperidone (HP 873), a potential atypical antipsychotic with dopamine D2/5-hydroxytryptamine2 receptor antagonist activity.

Iloperidone {HP 873: 1-[4-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3-methoxyphenyl]ethanone} is a dopamine (D2)/serotonin (5-HT2) receptor antagonist with the preclinical profile of an atypical antipsychotic based on biochemical studies in rats. Iloperidone significantly increased dopa accumulation, an index of dopamine turnover in response to D2 receptor blockade, at doses from 0.3 to 10 mg/kg i.p. in the striatum and from 1 to 10 mg/kg in the nucleus accumbens. Blockade of dopaminergic presynaptic autoreceptors was measured by the reversal of apomorphine-inhibition of gamma-butyrolactone-induced dopa synthesis. Iloperidone did not significantly reverse the apomorphine inhibition of gamma-butyrolactone-induced dopa synthesis at any of the doses tested (0.3-10 mg/kg i.p.). In ex vivo receptor autoradiography studies, a 30-min pretreatment with iloperidone (2.5-20 mg/kg i.p.) inhibited the binding of [3H]spiperone to cortical and subcortical 5-HT2 receptors by 42 to 94%, in contrast to only 1 to 15% inhibition of [3H]spiperone binding to D2 receptors in the nucleus accumbens and striatum. Iloperidone, at 2.5 mg/kg i.p., inhibited 5-HT2 receptor binding by 54 to 62% at 4-hr post-treatment, whereas there was negligible inhibition of D2 receptors. Chronic treatment with 5 mg/kg i.p. of iloperidone for 19 days significantly decreased the number of 5-HT2 receptors in the frontal cortex with no change in receptor affinity. D2 receptor number and affinity were unchanged in the nucleus accumbens and six regions of the striatum. In summary, iloperidone is a 5-HT and dopamine receptor antagonist with weak activity at presynaptic dopamine autoreceptors. Potent 5-HT2 receptor antagonism may be an important component in the preclinical profile of iloperidone as a potential atypical antipsychotic.

Effect of ritanserin on the interaction of amfonelic acid and neuroleptic-induced striatal dopamine metabolism.

In the present study we evaluated the interaction of amfonelic acid (AFA) with the typical neuroleptic haloperidol and the atypical antipsychotic clozapine on rat striatal dopamine metabolism in the absence or presence of the 5HT2 receptor antagonist ritanserin. In the absence of ritanserin, AFA significantly enhanced haloperidol stimulated 3,4- dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) accumulation by 36% and 37% respectively above that produced by haloperidol alone. This effect is believed to be due to AFA's ability to facilitate dopamine release produced by the potent haloperidol-induced increase in nigrostriatal impulse flow. In contrast, AFA did not potentiate the ability of clozapine to stimulate DOPAC or HVA. This lack of potentiation could be explained by clozapine's known potent 5HT2 receptor blocking activity attenuating its stimulatory effects on impulse flow. To test this, we combined ritanserin with haloperidol and again studied the interaction with AFA on dopamine metabolism. In the presence of ritanserin, AFA failed to potentiate the effects of haloperidol on DOPAC or HVA accumulation; an effect similar to that seen with clozapine. This result extends the idea that 5HT2 receptor blockade modulates nigrostriatal dopaminergic neurotransmission.

Sensitive high-performance liquid chromatographic method for the determination of chlorhexidine in human serum and urine.

A high-performance liquid chromatographic method for the analysis of chlorhexidine in human serum and urine was developed. Chlorhexidine and the internal standard, chlorpheniramine, were extracted into chloroform, containing 5% 2-propanol, and back-extracted into dilute sulfuric acid. Chromatographic separation was achieved on a C18 column equilibrated with methanol-water (70:30, v/v), containing 0.005 M sodium heptane-sulfonate. The sensitivity of the assay was 20 ng/ml of biological matrix, using 0.5-ml samples. The application of this method to monitor chlorhexidine levels in burn patients treated topically with a chlorhexidine-containing burn cream was demonstrated.

Synthesis of 8-aryltetrahydroisoquinolines as dopamine antagonists and evaluation for potential neuroleptic activity.

The synthesis of 8-(methoxyphenyl)-1,2,3,4-tetrahydroisoquinolines using aryloxazolines as key intermediates is described. Nucleophilic displacement on an o-methoxyphenyloxazoline by an aryl Grignard reagent, followed by electrophilic substitution at the other ortho position, provided a specific route to the properly substituted benzene intermediates necessary for conversion to the tetrahydroisoquinolines. These compounds and 8-phenyl- and 2-methyl-8-phenyl-1,2,3,4-tetrahydroisoquinolines, which are ring-opened analogues of apomorphine, were found to be dopamine antagonists by in vitro dopamine receptor studies. In vivo evaluation, however, did not substantiate potential usefulness as antipsychotic agents when they were compared with standard neuroleptic agents.

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.

Antidiarrheal and central nervous system activities of SC-27166 (2-[3 - 5 - methyl - 1, 3, 4 - oxadiazol - 2 - yl) - 3, 3 - diphenylpropyl] - 2 - azabicyclo [2.2.2]octane), a new antidiarrheal agent, resulting from binding to opiate receptor sites of brain and myenteric plexus.

Pharmacological studies were performed to investigate the interaction of SC-27166 (2-[3-(5-methyl-1,3,4--oxadiazol-2-yl)-3,3-diphenylpropyl]-2-azabicyclo[2.2.2]octane), a new antidiarrheal agent, with opiate receptor sites in vitro and in vivo. Morphine, loperamide and SC-27166 inhibited the binding of [3H]naloxone to homogenates of guinea-pig brain and myenteric plexus and the inhibition was diminished in the presence of 100 mM Na+. Unlike that of morphine and [3H]naloxone itself, the binding of loperamide and SC-27166 was complex and Scatchard plots indicated the presence of low and high affinity sites for both compounds. Morphine, loperamide and SC-27166 inhibited the contractions of electrically driven longitudinal muscle from guinea-pig ileum and naloxone antagonized these effects. In the anesthetized dog, i.v. administration of morphine and SC-27166 enhanced the contractile activity of circular muscle in proximal and distal duodenum and distal ileum but duodenal longitudinal muscle was relaxed; these effects were completely reversed by subsequent administration of naloxone. In the rat, p.o. administration of loperamide and SC-27166 inhibited intestinal propulsion at doses considerably lower than were necessary to produce activity in the hot plate test; this specificity of action was not seen with morphine. In the rat, p.o. administration of loperamide and SC-27166 inhibited diarrhea at doses considerably lower than were necessary to produce withdrawal symptoms. The authors concluded that both loperamide and SC-27166 are specific antidiarrheal agents that produce both their central and antidiarrheal effects by binding to opiate receptor sites.