Craig P. Smith

Animal models with potential applications for screening compounds for the treatment of obsessive-compulsive disorder

The availability of an animal model for obsessive-compulsive disorder (OCD) is necessary for the development of novel pharmacological treatments. To be useful, the model must be predictive of clinical performance, possess characteristic criteria and distinguish anti-OCD from antidepressant compounds. Due to the lack of OCD models useful for drug discovery, all compounds currently used for OCD were developed first as antidepressants. In this article, we discuss the relative merits of: stereotypic behaviours (canine acral lick, feather picking, amphetamine- and 5-HT-induced stereotypy); adjunctive and displacement behaviours (schedule-induced polydipsia, wheel running, resident-intruder grooming); anxiolytic tests (separation and shock-induced ultrasonic vocalisation and marble burying); and depression tests (inescapable shock-induced escape and immobility in forced swim) as potential OCD models. We conclude that adjunctive and displacement behaviours, and in particular schedule-induced polydipsia, may prove to be the best models for compulsive behaviour in animals that can be used for the discovery of novel anti-OCD agents.

Synthesis and preliminary structure-activity relationships of 1-[(3-fluoro-4-pyridinyl)amino]-3-methyl-1H-indol-5-yl methyl carbamate (P10358), a novel acetylcholinesterase inhibitor

Abstract A series of carbamate analogs of besipirdine (HP 749) was synthesized as potential agents with enhanced cholinomimetic properties for the treatment of Alzheimers disease. Compound 5a (P10358, 1-[3-fluoro-4-pyridinyl)amino]-3-methyl-1H-indol-5-yl methyl carbamate) emerged as a potent, reversible acetylcholinesterase inhibitor that significantly enhanced performance on oral or parenteral administration in learning and memory paradigms.

In Vitro electrophysiological activity of nerispirdine, a novel 4-aminopyridine derivative

1 The non‐selective K+ channel blocker 4‐aminopyridine (4‐AP) has shown clinical efficacy in the treatment of neurological disorders such as multiple sclerosis. The clinical usefulness of 4‐AP is hampered by its ability to produce seizures. Nerispirdine, an analogue of 4‐AP, is currently under clinical investigation for the treatment of multiple sclerosis. In contrast with 4‐AP, nerispirdine is not proconvulsant, suggesting mechanistic differences between the two drugs. 2 Using whole‐cell patch‐clamp electrophysiology, we compared the effects of 4‐AP and nerispirdine on the cloned human K+ channels Kv1.1 and Kv1.2, expressed in Chinese hamster ovary cells, and on voltage‐dependent Na+ channels recorded from human SH‐SY5Y cells. 3 Nerispirdine inhibited Kv1.1 and Kv1.2 with IC50 values of 3.6 and 3.7 μmol/L, respectively. 4‐Aminopyridine was approximately 50‐fold less potent at blocking these channels. Nerispirdine also inhibited voltage‐dependent Na+ channel currents recorded from human SH‐SY5Y cells with an IC50 of 11.9 μmol/L when measured from a –70 mV holding potential. In contrast, 4‐AP had no effect on Na+ channel currents. 4 The results demonstrate that nerispirdine, like 4‐AP, can inhibit axonal K+ channels and that this mechanism may underlie the ability of the drug to enhance neuronal conduction. Unlike 4‐AP, nerispirdine can also inhibit neuronal Na+ channels, a mechanism that may explain why nerispirdine lacks proconvulsant activity.

Serotonergic activity of HP 184: does spontaneous release have a role?

Examination of HP 184, [N-n-propyl)-N-(3-fluoro-4-pyridinyl)-1H-3-methylindodel-1-amine hydrochloride], in a variety of tests for serotonergic activity revealed some unique properties of this compound. We report here that 100 μM HP 184 enhanced spontaneous release of [3H]serotonin (5-HT) from rat hippocampal slices. This release was independent of the uptake carrier. In vivo assays confirmed that HP 184 (20 mg/kg, i.p.) lacked significant interactions at the norepinephrine (NE) or 5-HT uptake carrier itself. Notably, HP 184 (15 mg/kg, i.p.) reduced drinking behavior in schedule-induced polydipsic (SIP) rats. We previously reported that some selective 5-HT reuptake inhibitors decrease SIP 30–40% after a 14–21 day treatment. In the current study, HP 184 decreased SIP beginning with the first treatment, and this reduction (30%) was maintained for 28 days. We further investigated HP 184 and serotonin metabolite levels. One hour after i.p. administration of 30 mg/kg HP 184, the ratio of whole brain 5-hydroxyindolacetic acid (5-HIAA) to 5-HT was increased, suggesting serotonergic activation. Under these conditions, the brain: plasma ratio of HP 184 was approximately 2∶1, with brain concentrations of 1.6 μg/gram. We speculate that the spontaneous release effects of HP 184 may be responsible for the behavioral effects observed.

HP 749 enhances calcium-independent release of [3H]norepinephrine from rat cortical slices and synaptosomes.

Previous studies have shown that, at concentrations of 1 μM and 10 μM, HP 749 increased electrically-stimulated release of [3H]norepinephrine (NE) from rat cortical slices. These effects were Ca2+-dependent, indicating an effect on release from vesicular stores. At 100 μM, HP 749 had two effects. In addition to enhancing the Ca2+-dependent electrically-evoked release, it also induced a rise in the basal efflux (spontaneous release) of [3H]NE, which was observed in both cortical slices and synaptosomes. The spontaneous release effect was (1) not blocked by the reuptake inhibitor nomifensine, (2) not affected by removal of external calcium, (3) not blocked by vesicular depletion with reserpine, and (4) not inhibited by the sodium channel blocker tetrodotoxin (TTX). As would be expected, the spontaneous [3H]NE release induced by the cytoplasmic releaser tyramine and the sodium channel activator veratridine were blocked by nomifensine and TTX, respectively. Notably, however, the Ca2+-independent veratridine-induced release was completely blocked by 100 μM HP 749. The mechanism of spontaneous release of [3H]NE caused by 100 μM HP 749 is unresolved at present; however, the data are consistent with this release originating from a cytoplasmic source.

4-aminopyridine derivatives: A family of novel modulators of voltage-dependent sodium channels

The interactions of a family of aminopyridine derivatives with Site II of the voltage‐dependent sodium channel were examined by measuring the ability of these compounds to inhibit [3H]batrachotoxin binding and veratridine‐induced increases in [Ca2+]i. Aminopyridines substituted with indole, carbazole, and pyrrole rings were evaluated. All compounds that had an aromatic ring linked to the amine group of 4‐aminopyridine showed positive results in both assays. For example, the most potent compound, besipirdine (N‐(n‐propyl)‐N‐(4‐pyridinyl)‐1H‐indol‐1‐amine), had IC50 values of 5 μM and 23.8 μM in the two assays, respectively. Small substitutions on either the aromatic ring or on 4‐aminopyridine did not substantially change their potencies. Indoles linked to the amino group of 2‐ and 3‐aminopyridine also showed positive results. These results indicate that aminopyridine derivatives substituted with an aromatic ring on the amino nitrogen are inhibitors of voltage‐dependent sodium channels. Drug Dev. Res. 44:8–13, 1998.

P11467: An Orally-Active Acetylcholinesterase Inhibitor and α 2 -Adrenoceptor Antagonist for Alzheimer’s Disease

Alzheimer’s disease (AD) is a complex and multifaceted neurodegenerative disease characterized by cognitive and behavioral abnormalities. The primary cognitive deficit has been correlated with extensive cholinergic dysfunction and the efficacy of cholinergic therapies in this disease validates and supports the cholinergic hypothesis of AD (Weinstock, 1995). To date, tacrine has shown clinical efficacy in 20 to 30% of AD patients and remains the only acetylcholinesterase inhibitor (AChEI) to receive FDA approval for symptomatic treatment (Knapp et al., 1994). However, the limited efficacy of pure cholinergic therapies suggests that other neurochemical deficiencies are involved.