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1.
J Med Chem ; 44(3): 372-89, 2001 Feb 01.
Article in English | MEDLINE | ID: mdl-11462978

ABSTRACT

A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.


Subject(s)
Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Dibenzothiazepines/pharmacology , Dopamine Antagonists/pharmacology , Dyskinesia, Drug-Induced/etiology , Receptors, Dopamine D2/drug effects , Animals , Antipsychotic Agents/adverse effects , Antipsychotic Agents/chemistry , Apomorphine/pharmacology , Cebus , Dibenzothiazepines/adverse effects , Dibenzothiazepines/chemistry , Dopamine Antagonists/adverse effects , Dopamine Antagonists/chemistry , Female , Male , Mice , Quetiapine Fumarate , Stereoisomerism , Structure-Activity Relationship
2.
Br J Pharmacol ; 113(2): 379-84, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7834187

ABSTRACT

1. Verapamil and emopamil are structurally related phenylalkylamine calcium channel/5-HT2 receptor antagonists that differ in their anti-ischaemic properties in experimental studies. The quaternary ammonium derivatives of these compounds were prepared and tested in assays of neuronal voltage-sensitive calcium channel (VSCC) function to determine whether the compounds act at intra- or extracellular sites. 2. The compounds were tested in K(+)-evoked: (1) rat brain synaptosomal 45Ca2+ influx, (2) release of [3H]-D-aspartate from rat hippocampal brain slices and (3) increase of intracellular calcium in rat cortical neurones in primary culture. 3. Verapamil, emopamil and the emopamil quaternary derivative caused concentration-dependent and comparable (IC50 values approximately 30 microM) inhibition of synaptosomal 45Ca2+ influx and [3H]-D-aspartate release. The verapamil quaternary derivative was considerably less active in these assays (IC50 > 300 microM). 4. The evoked increase of intracellular calcium in cortical neurones was inhibited with the following rank order of potency (IC50 value, microM): emopamil (3.6) > verapamil (17) > emopamil quaternary derivative (38) > verapamil quaternary derivative (200). 5. The results suggest that verapamil and emopamil inhibit nerve terminal VSCC function (synaptosomal 45Ca2+ influx and [3H]-D-aspartate release) by acting at distinct intracellular and extracellular sites, respectively. Verapamil and emopamil may inhibit cell body VSCC function (evoked increase of intracellular calcium in neocortical neurones) by acting at both intracellular and extracellular sites. 6. The different 'sidedness' of action of emopamil and verapamil on nerve terminal VSCC function and/or the preferential inhibition of cell body VSCC function by emopamil may at least partially explain the relatively greater neuroprotective efficacy of emopamil in experimental models of ischaemia.


Subject(s)
Aspartic Acid/metabolism , Calcium Channel Blockers/pharmacology , Calcium/metabolism , Neurons/metabolism , Verapamil/analogs & derivatives , Animals , Calcium Radioisotopes , Electrophysiology , Hippocampus/drug effects , Hippocampus/metabolism , In Vitro Techniques , Neurons/drug effects , Potassium/pharmacology , Rats , Synaptosomes/drug effects , Synaptosomes/metabolism , Verapamil/pharmacology
3.
Psychopharmacology (Berl) ; 112(2-3): 299-307, 1993.
Article in English | MEDLINE | ID: mdl-7871034

ABSTRACT

Seroquel was compared to clozapine and several other antipsychotic agents in tests predictive of antipsychotic activity or extrapyramidal symptoms. In the conditioned avoidance test in squirrel monkeys as well as several paradigms using apomorphine or amphetamine-induced behavioral alterations, seroquel displayed the profile of a drug with potential antipsychotic activity. In these paradigms the potency of seroquel was somewhat less than clozapine in rodent tests, while the reverse was true in higher species, i.e. monkeys, cats. In tests designed to evaluate the propensity to induce EPS or tardive dyskinesia, for example, the production of dyskinetic reactions in haloperidol-sensitized cebus monkeys, seroquel displayed a profile similar to clozapine and disparate from typical antipsychotic drugs. In drug-naive cebus monkeys seroquel sensitized significantly fewer monkeys than haloperidol and the dyskinetic reactions were of significantly less intensity. It is anticipated that this novel antipsychotic agent will have a significantly reduced propensity to produce extrapyramidal symptoms and tardive dyskinesia than typical antipsychotics.


Subject(s)
Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Dibenzothiazepines/pharmacology , Amphetamine/antagonists & inhibitors , Amphetamine/pharmacology , Animals , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Avoidance Learning/drug effects , Basal Ganglia Diseases/chemically induced , Basal Ganglia Diseases/physiopathology , Catalepsy/chemically induced , Catalepsy/psychology , Cats , Cebus , Dyskinesia, Drug-Induced/physiopathology , Female , Fixation, Ocular/drug effects , Male , Mice , Motor Activity/drug effects , Quetiapine Fumarate , Rats , Rats, Sprague-Dawley , Saimiri , Stereotyped Behavior/drug effects , Swimming
4.
J Med Chem ; 18(6): 587-93, 1975 Jun.
Article in English | MEDLINE | ID: mdl-1151973

ABSTRACT

A number of 3-amino-2-benzhydrylquinuclidines were tested for diuretic activity in both rats and dogs. The Schiff base formed from 2-benzhydryl-3-quinuclidinone and benzylamine was reduced with NaBH4 to a mixture of isomers, the cis isomer being preponderants. cis-2-Benzhydryl-3-benzylaminoquinuclidine was isolated by chromatography and debenzylat:d to cis-3-amino-2-benzhydrylquinuclidine, the most active compound in this series. The corresponding trans isomer was considerably less active. It was made by reacting the mesylate of cis-2-benzhydr-l-3-quinuclidinol with Nan3 to form trans-3-azido-2-benzhydrylquinuclidine which was reduced with LiAlH4. In dose-response studies (sodium excretion as a function of dose) in rats the maximal or ceiling effect of cis-3-amino-2-benzhydrylquinuclidine was considerably greater than that of hydroflumethiazide but less than that of furosemide. An unusual biphasic dose-response was seen in dogs with cis-3-amino-2-bezhydrylquinuclidine, centering around 10 mg/kg.


Subject(s)
Diuretics/chemical synthesis , Quinuclidines/chemical synthesis , Animals , Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/pharmacology , Chlorides/urine , Diuresis/drug effects , Diuretics/pharmacology , Dogs , Dose-Response Relationship, Drug , Furosemide/pharmacology , Hydroflumethiazide/pharmacology , Potassium/urine , Quinuclidines/pharmacology , Rats , Sodium/urine , Stereoisomerism , Structure-Activity Relationship
5.
J Med Chem ; 18(1): 71-4, 1975 Jan.
Article in English | MEDLINE | ID: mdl-803245

ABSTRACT

The 1,4 addition of p-chlorophenylmagnesium bromide to 2-benzylidene-3-quinuclidinone gave 2-(4-chlorobenzhydryl)-3-quinuclidinone as two diastereoisomers. Selective reduction of this ketone with aluminum isopropoxide gave the two cis-2-(4-chlorobenzhydryl)-3-quinuclidinols, which differ only in the configuration of the benzhydryl group, designated alpha and beta in order of their elution on chromatography. Reduction with NaBH4 gave a mixture of four isomeric alcohols, of which the two cis isomers were selectively oxidized. The two trans-2-(4-chlorobenzhydryl)-3-quinuclidinols were chromatographically separated and desingated alpha and beta in order of elution. Only the beta-cis and beta-trans alcohols showed CNS stimulant properties. The beta-cis isomer was shown to be related both qualitatively and quantitatively more to methylphenidate (Ritalin) than to d-amphetamine.


Subject(s)
Central Nervous System/drug effects , Quinuclidines/chemical synthesis , Animals , Appetite/drug effects , Appetite Depressants/chemical synthesis , Appetite Depressants/pharmacology , Behavior, Animal/drug effects , Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/pharmacology , Benzhydryl Compounds/toxicity , Blood Pressure/drug effects , Dextroamphetamine/pharmacology , Dextroamphetamine/toxicity , Dogs , Haplorhini , Lethal Dose 50 , Male , Methylphenidate/pharmacology , Methylphenidate/toxicity , Mice , Quinuclidines/pharmacology , Quinuclidines/toxicity , Rats , Stimulation, Chemical
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