Structure-activity relationships of a series of novel (piperazinylbutyl)thiazolidinone antipsychotic agents related to 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5- trimethyl-4-thiazolidinone maleate.

HP-236 (3-[4-[4-(6-Fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5- trimethyl-4-thiazolidinone maleate; P-9236) (54) displayed a pharmacological profile indicative of potential atypical antipsychotic activity. A series of piperazinyl butyl thiazolidinones structurally related to this compound were prepared and evaluated in vitro for dopamine D2 and serotonin 5HT2 and 5HT1A receptor affinity. The compounds were examined in vivo in animal models of potential antipsychotic activity and screened in models predictive of extrapyramidal side effect (EPS) liability. The synthesis of these compounds, details of their structure-activity relationships, and discovery of a new lead, compound 50, as well as further development of the profiles of compounds 50 and 54 are described.

Besipirdine (HP 749) reduces schedule-induced polydipsia in rats.

The aim of the present paper is to report on the adrenergic and serotonergic effects of besipirdine (HP 749) in vivo and to discuss its potential use in the treatment of obsessive compulsive disorder. Besipirdine inhibited biogenic amine uptake in vitro. It prevented tetrabenazine-induced ptosis in mice and potentiated the 5-hydroxytryptophan-induced serotonin syndrome in rats. Furthermore, it decreased schedule-induced polydipsic behavior in rats. Schedule-induced polydipsia may be a model for obsessive compulsive disorder. Previous results from our group have shown that certain selective serotonin reuptake inhibitors decrease schedule-induced polydipsia after 14-21 days of treatment. Besipirdine reduced schedule-induced polydipsic behavior immediately and this reduction lasted throughout the duration of the experiment (29 days).

The pharmacological profile of iloperidone, a novel atypical antipsychotic agent.

Iloperidone (1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone) demonstrated a potent antipsychotic profile in several in vitro and in vivo animal models. Iloperidone displaced ligand binding at D2 dopamine receptors (IC50 = 0.11 microM) and displayed a high affinity for serotonin (5-HT2) receptors (IC50 = 0.011 microM) and alpha-1 receptors (IC50 = 0.00037 microM). In vivo, iloperidone antagonized apomorphine-induced climbing behavior in mice at low doses with good oral bioavailability, prevented 5-HT-induced head twitch in rats at low doses, and inhibited self-stimulation behavior in rats, pole climb avoidance in rats and continuous Sidman avoidance responding in monkeys. The latter assay also demonstrated a good duration of action. Iloperidone was substantially less active in models of extrapyramidal side effect (EPS) liability, such as preventing apomorphine-induced stereotypy and causing catalepsy in rats. In single dopamine neuron sampling studies, iloperidone demonstrated clozapine-like effects on the number of active midbrain dopamine neurons. Based on the significant increase in the open arm time seen after iloperidone treatment in the elevated plus maze assay and increased interaction score in social interaction, iloperidone may also have favorable effects in the clinic on anxiety and, possibly, negative symptoms. Clinical trials are under way of the use of iloperidone for the treatment of schizophrenia.

3-[[(Aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles as D2/5-HT2 antagonists with potential atypical antipsychotic activity: antipsychotic profile of iloperidone (HP 873).

A series of 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles was synthesized and evaluated as potential antipsychotic D2/5-HT2 antagonists. Most of these compounds showed potent antipsychotic-like activity in an apomorphine-induced climbing mouse paradigm, with many also showing preferential mesolimbic activity, as indicated by their weaker effects in an apomorphine-induced stereotypy model. In receptor binding assays, many displayed a moderate affinity for the D2 receptor coupled with a significantly greater affinity for the 5-HT2 receptor: a property that has been suggested as necessary for atypicality. From this series, compound 45, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone (iloperidone, HP 873), was further evaluated in a battery of in vivo and in vitro assays. This compound showed a 300-fold greater potency in inhibition of climbing than in inhibition of stereotypy or induction of catalepsy, and when evaluated chronically in an electrophysiological model, 45 caused a depolarization blockade of dopamine neurons in the A10 area of the rat brain but not in the A9 area. Additionally, it showed positive activity in a social interaction paradigm, suggesting potential efficacy against asociality, a component of the negative symptoms of schizophrenia. In chronic ex vivo studies, 45, similar to clozapine, caused a down regulation of 5-HT2 receptors but had no effect on the number of D2 receptors. Compound 45 is currently undergoing clinical evaluation.

9-Amino-1,2,3,4-tetrahydroacridin-1-ols: synthesis and evaluation as potential Alzheimer's disease therapeutics.

The synthesis of a series of 9-amino-1,2,3,4-tetrahydroacridin-1-ols is reported. These compounds are related to 1,2,3,4-tetrahydro-9-acridinamine (THA, tacrine). They inhibit acetylcholinesterase in vitro and are active in a model that may be predictive of activity in Alzheimer's disease--the scopolamine-induced impairment of 24-h memory of a passive dark-avoidance paradigm in mice. Two compounds, (+/-)-9-amino-1,2,3,4-tetrahydroacridin-1-ol maleate (1a, HP-029) and (+/-)-9-(benzylamino)-1,2,3,4-tetrahydroacridin-1-ol maleate (1p, HP-128), were also active in reversing the deficit in 72-h retention of a one-trial dark-avoidance task in rats, induced by ibotenic acid lesions in the nucleus basalis magnocellularis. In addition, compound 1 p showed potent in vitro inhibition of the uptake of radiolabeled noradrenaline and dopamine (IC50 = 0.070 and 0.30 microM, respectively). Compounds 1a and 1p, which showed less acute toxicity in both rats and mice than THA, are in phase II and phase I clinical trials, respectively, for Alzheimer's disease.

Opiate-induced turning in rats after injection into the ventral tegmental area.

Morphine and ethylketazocine caused ipsilateral circling when injected unilaterally into the ventral tegmental area (VTA) of rats. Systemic naloxone only slightly inhibited this effect while systemic diprenorphine completely prevented circling. Systemic haloperidol and alpha-methyl-p-tyrosine also blocked circling. Rats made tolerant to morphine still turned after morphine injection into the VTA. Levorphanol, dextrorphan, methadone, DADLE, dynorphin(1-13), SKF 10,047 and phencyclidine were inactive when injected unilaterally into the VTA of naive rats; naloxone and naltrexone alone also were inactive. The opiate-induced circling appears to involve a non-mu opiate receptor as well as a dopaminergic neuronal system.

Pharmacology of nomifensine: a review of animal studies.

Nomifensine has demonstrated efficacy in several animal models that have been found to be predictive of clinical antidepressant activity, and has also been found to have a low potential for both cardiovascular and anticholinergic side effects. A comparison of nomifensine's profile with those of standard antidepressant agents shows this drug to possess clear advantages which may make it an attractive choice for the treatment of endogenous depression.