James Heym

The substance P receptor antagonist CP-96,345 interacts with Ca2+ channels

The nonpeptide substance P receptor antagonist CP-96,345 was found to displace binding to Ca2+ channel binding sites labelled with either [3H]desmethoxyverapamil or [3H]diltiazem and to enhance [3H]nitrendipine binding. Unlike the substance P receptor antagonist activity of CP-96,345, these effects on Ca2+ channel binding sites were neither stereoselective nor species-dependent. It is concluded that CP-96,345 may act as an antagonist of L-type Ca2+ channels in addition to being a potent NK1 receptor (substance P) antagonist.

Comparison of the effects of sertraline and its metabolite desmethylsertraline on blockade of central 5-HT reuptake in vivo

N-demethylation of the selective serotonin reuptake inhibitor sertraline to desmethylsertraline yields a compound with 10- to 20-fold less potency at blocking serotonin (5-HT) reuptake as measured in vitro. In the present study desmethylsertraline (DMS) was examined in two in vivo models of reuptake inhibition—elevation of extracellular 5-HT in the corpus striatum as measured by microdialysis and inhibition of firing of serotonin-containing dorsal raphe neurons. Whereas sertraline (1, 3.2, and 10 mg/kg SC) produced a dose-dependent increase in extracellular 5-HT and a decrease in 5-HIAA in rat striatum, desmethylsertraline was without effect on either parameter. In similar fashion, desmethylsertraline had no effect on dorsal raphe cell firing at a dose (1,000 μg/kg IV) nearly 20-fold the ED50 for sertraline (52 μg/kg). Taken together, these data suggest that DMS does not contribute to the blockade of central 5-HT reuptake produced by sertraline in vivo and therefore would be expected to play a negligible role in its clinical activity.

Chapter 3. Antidepressant Agents

Publisher Summary This chapter discusses the several recent reviews that cover various aspects of depression and antidepressant research. The research on selective inhibitors of serotonin (5HT) uptake relative to their effects on the uptake of dopamine (DA) or norepinephrine (NE) has led to the successful development of selective serotonin reuptake inhibitors (SRIs) as antidepressants. The results with fluoxetine seem to characterize the SRIs as a whole, efficacy equivalent to tricyclic antidepressants (TCAs), but often with better toleration because of a different spectrum of side effects. The advantage offered by fluoxetine, therefore, relates to a more benign side effect profile that makes it a more useful agent for some depressed patients. Semaline has proven to be a well tolerated and efficacious antidepressant in a number of trials and its preclinical biology has been reviewed. Paroxetine, one of the more potent 5HT uptake inhibitors in vitro , has shown antidepressant activity in a controlled clinical trial. It is also observed that SRIs produce positive results in treating obsessive compulsive disorder. Although one of the oldest classes of antidepressants, irreversible monoamine oxidase inhibitors (MAO), such as phenelzine and tranylcypromine, have had limited use because of a severe hypertensive crisis. However, recent reviews have appeared that cover the current biological understanding of MAO and the role of MAO inhibition in the treatment of depression. Current research now suggests that reversible and selective inhibition of MAO-A will afford antidepressant activity without hypertensive side effects. Buspirone, gepirone, SM-3997, and ipsapirone represent a new class of non-benzodiazepine anxiolytics that have also demonstrated promise as antidepressants. Further reports on rolipram, the prototype of this new class of antidepressants, have been encouraging. The potential for new therapies of depression and affective disorders has emerged from research around lithium, corticotropin-releasing factor (CRF), and S-adenosyl methionine.

CP-93,129: A Potent and Selective Agonist for the Serotonin (5-HT1B) Receptor and Rotationally Restricted Analog of RU-24,969

The in vitro and in vivo characteristics of CP-93,129 [Structure 1 in Figure 1, 3-(1,2,5,6-tetrahydropyrid-4-yl)-pyrrolo[3,2-b]pyrid-5-one] are described. This rotationally restricted phenolic analog of RU-24,969 is a potent (15 nm) and selective (200 × vs. the 5-HT1A receptor, 150 × vs. the 5-HT1D receptor) functional agonist for the 5-HT1B receptor. Direct infusion of CP-93, I29 into the paraventricular nucleus of the hypothalamus of rats significantly inhibits food intake, implicating the role of 5-HT1B receptors in regularing feeding behavior in rodents. CP-93,129 has also been shown to be biochemically discriminatory in its ability to selectively inhibit forskolin-stimulated adenylate cyclase activity only at the 5-HT1B receptor. The source of the selectivity of CP-93,129 appears to lie in the ability of a pyrrolo[3,2-b]pyrid5-one to act as a rotationally restricted bioisosteric replacement for 5-hydroxyindole.

Chapter 1 Antipsychotic Agents

Publisher Summary The organic pathology underlying chronic schizophrenia, which remains a devastating mental disorder, has emerged as a major topic of discussion. It presents an extremely difficult challenge for the discovery of safe and effective therapeutics. Recent studies, employing positron emission tomography have provided clear evidence of dopamine (DA) receptor proliferation in untreated schizophrenics. This finding may be an important underpinning for the DA hypothesis of schizophrenia, especially in light of the fact that DA antagonists are still the only established pharmacotherapy for psychosis. Nevertheless, anti-psychotic medications leave much to be desired, in terms of both efficacy and side effect profile. Consequently, the search continues for DA antagonists with improved therapeutic ratios as well as novel agents that can attenuate dopaminergic neurotransmission without direct interaction at DA receptors. Neuroleptic drugs are effective against the florid symptoms of psychosis. The benzamide neuroleptics form a distinct class of drugs on the basis of two attributes— that is, structural commonality and selectivity for D 2 DA receptors. Substituted benzamides have exhibited varying propensities to induce extrapyramidal side effects (EPS). Such drugs, for example, metoclopramide, resembles with classical neuroleptics with regard to EPS liability, while remoxipride also being similar in efficacy to classical agents but causes less severe EPS. It is recently observed to be a very selective, low potency D 2 blocker in vitro . Remoxipride preferentially inhibits the binding of [ 3 H]spiperone to DA receptors in limbic regions(rat brain). Striatal DA receptors are blocked only to the extent of 60%, even at very high drug doses. Raclopride possesses very high affinity for D 2 receptors in vitro and binds preferentially to the striatum in the rat in vivo . While neuroleptic drugs are effective against the florid symptoms of psychosis, negative symptoms of schizophrenia, such as social withdrawal and cognitive decline, remain uncontrolled.