Edward John Warawa

Seroquel : Behavioral effects in conventional and novel tests for atypical antipsychotic drug

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.

Behavioral approach to nondyskinetic dopamine antagonists: identification of seroquel.

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.

Extracellular site for econazole-mediated block of Ca2+ release-activated Ca2+ current (Icrac) in T lymphocytes

1 Standard whole cell patch clamp recording techniques were used to study the pharmacological characteristics and site of econazole‐mediated inhibition of calcium release‐activated calcium current (Icrac) in the human leukaemic T cell line, Jurkat. 2 Extracellularly applied econazole blocked Icrac in a concentration‐dependent manner (IC50 ≅ 14 μm). Block developed over a relatively slow timecourse of 30–60 s (10 μm), and only partially reversed over minutes. 3 Econazole dialysed from the pipette into the cytosol at concentrations ranging from 0.1 to 30 μm did not reduce Icrac, or quantitatively affect Icrac block by extracellularly applied econazole. 4 A less lipophilic quaternary iodide derivative of econazole was synthesized to retard absorption through the cell membrane. When applied extracellularly, this compound blocked Icrac in a concentration‐dependent manner with onset kinetics comparable to econazole. 5 Results with intracellularly dialysed econazole and the quaternary econazole derivative provide convergent evidence that econazole blocks Icrac via an extracellular interaction. 6 The inability of intracellularly applied econazole to inhibit Icrac argues against the notion that econazole inhibits capacitative Ca2+ entry pathways secondary to its known inhibitory effects on cytochrome P‐450.

Differential inhibition of neuronal calcium entry and [3H]-D-aspartate release by the quaternary derivatives of verapamil and emopamil.

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 −30 μm) inhibition of synaptosomal 45Ca2+ influx and [3H]‐D‐aspartate release. The verapamil quaternary derivative was considerably less active in these assays (IC50 > 300 μm). 4 The evoked increase of intracellular calcium in cortical neurones was inhibited with the following rank order of potency (IC50 value, μm): 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.