Examination of the mechanisms underlying the discriminative stimulus properties of the atypical antipsychotic amisulpride.

Amisulpride is an atypical benzamide antipsychotic/antidepressant, whose mechanism of action is thought to depend mainly on dopamine D2/3 receptor activity, but also with some serotonin 5-HT2B/7 effects. The present study examined the role of D2/3 receptors and 5-HT2B/7 receptors in amisulpride's discriminative stimulus. Selective agonists and antagonists of the above receptors were tested in adult, male C57BL/6 mice trained to discriminate 10 mg/kg amisulpride from vehicle in a two-lever drug discrimination assay. After acquisition of the two-lever discrimination, the amisulpride generalization curve yielded an ED50 = 0.56 mg/kg (95% CI = 0.42-0.76 mg/kg). Substitution tests found that the D2/3 antagonist raclopride (62.7% Drug Lever Responding), D2/3 agonist quinpirole (56.6% DLR), 5-HT7 agonist LP-44 (50.1% DLR) and 5-HT7 antagonist SB-269970 (36.7% DLR) produced various degrees of partial substitution for the amisulpride stimulus, whereas the 5-HT2B agonist BW 723C86 (17.9% DLR) and 5-HT2B antagonist SB-204741 (21.1% DLR) yielded negligible amisulpride-like effects. In combination tests with amisulpride, quinpirole decreased percent responding from 98.3% to 57.0% DLR, LP-44 decreased percent responding from 97.6% to 76.7% DLR, and BW 723C86 reduced percent responding from 95.66% to 74.11% DLR. Taken together, the results from stimulus generalization and antagonism studies suggest that amisulpride has a complex discriminative cue that involves mainly mixed D2/3 receptor antagonist/agonist effects and, to a lesser degree, mixed 5-HT7 receptor agonist/antagonist and perhaps 5-HT2B receptor antagonist effects.

Discriminative stimulus properties of the typical antipsychotic haloperidol compared to other antipsychotic drugs in C57BL/6 mice.

Haloperidol (HAL) was developed in 1958 for the treatment of schizophrenia and is classified as a typical antipsychotic drug (APD). Effective in treating positive symptoms of schizophrenia, it does not treat negative symptoms and produces extrapyramidal motor side-effects. Atypical APDs like clozapine treat both positive and negative symptoms of schizophrenia, have reduced extrapyramidal motor side-effects and possess other clinical advantages. This study used a drug discrimination assay to allow a direct comparison between the subjective effects of HAL and other APDs. Eleven C57BL/6 mice were trained to discriminate 0.05 mg/kg HAL from the vehicle in a two-lever drug discrimination task. The HAL generalization curve (0.001563-0.2 mg/kg) yielded an ED50=0.0024 mg/kg (95% confidence interval: 0.0012-0.0048 mg/kg). The typical APD chlorpromazine produced full substitution at 4.0 mg/kg with 82.7% drug-lever responding (%DLR) with significant rate suppression and partial substitution (73.9% DLR) at 1.0 mg/kg with no rate suppression. The atypical APD clozapine produced partial substitution at 2.5 mg/kg (64.8% DLR) with significant rate suppression. The atypical APD amisulpride failed to substitute for HAL with a maximum %DLR of 57.9% at 40 mg/kg with no rate suppression. The atypical APD aripiprazole partially substituted with a maximum of 75.9% DLR at 1.25 mg/kg with significant rate suppression. These results demonstrate that HAL can be trained as a discriminative stimulus in C57BL/6 mice, and its discriminative cue appears to be unique and distinct from that of atypical APDs.

Effect of the leukotriene A4 hydrolase aminopeptidase augmentor 4-methoxydiphenylmethane in a pre-clinical model of pulmonary emphysema.

The leukotriene A(4) hydrolase enzyme is a dual functioning enzyme with the following two catalytic activities: an epoxide hydrolase function that transforms the lipid metabolite leukotriene A(4) to leukotriene B(4) and an aminopeptidase function that hydrolyzes short peptides. To date, all drug discovery efforts have focused on the epoxide hydrolase activity of the enzyme, because of extensive biological characterization of the pro-inflammatory properties of its metabolite, leukotriene B(4). Herein, we have designed a small molecule, 4-methoxydiphenylmethane, as a pharmacological agent that is bioavailable and augments the aminopeptidase activity of the leukotriene A(4) hydrolase enzyme. Pre-clinical evaluation of our drug showed protection against intranasal elastase-induced pulmonary emphysema in murine models.

Synthesis and evaluation of hermitamides A and B as human voltage-gated sodium channel blockers.

Hermitamides A and B are lipopeptides isolated from a Papau New Guinea collection of the marine cyanobacterium Lyngbya majuscula. We hypothesized that the hermitamides are ligands for the human voltage-gated sodium channel (hNa(V)) based on their structural similarity to the jamaicamides. Herein, we describe the nonracemic total synthesis of hermitamides A and B and their epimers. We report the ability of the hermitamides to displace [(3)H]-BTX at 10 µM more potently than phenytoin, a clinically used sodium channel blocker. We also present a potential binding mode for (S)-hermitamide B in the BTX-binding site and electrophysiology showing that these compounds are potent blockers of the hNav1.2 voltage-gated sodium channel.

Discriminative stimulus properties of the atypical antipsychotic amisulpride: comparison to its isomers and to other benzamide derivatives, antipsychotic, antidepressant, and antianxiety drugs in C57BL/6 mice.

RATIONALE: Racemic (RS)-amisulpride (Solian®) is an atypical antipsychotic drug used to treat schizophrenia and dysthymia. Blockade of dopamine D2/D3 and/or serotonin 5-HT7 receptors is implicated in its pharmacological effects. While the (S)-amisulpride isomer possesses a robust discriminative cue, discriminative stimulus properties of (RS)-amisulpride have not been evaluated. OBJECTIVES: The present study established (RS)-amisulpride as a discriminative stimulus and assessed amisulpride-like effects of amisulpride stereoisomers, other benzamide derivatives, and antipsychotic, antidepressant, and anxiolytic drugs. METHODS: Adult, male C57BL/6 mice were trained to discriminate 10 mg/kg (RS)-amisulpride from vehicle in a two-lever food-reinforced operant conditioning task. RESULTS: (RS)-Amisulpride's discriminative stimulus was dose-related, time-dependent, and stereoselective. (S)-Amisulpride (an effective dose of 50% (ED50) = 0.21 mg/kg) was three times more potent than (RS)-amisulpride (ED50 = 0.60 mg/kg) or (R)-amisulpride (ED50 = 0.68 mg/kg). (RS)-Amisulpride generalized fully to the structurally related atypical antipsychotic/antidysthymia drug sulpiride (Sulpor®; ED50 = 7.29 mg/kg) and its (S)-enantiomer (ED50 = 9.12 mg/kg); moderate to high partial generalization [60-75% drug lever responding (%DLR)] occurred to the benzamide analogs tiapride (Tiapridal®) and raclopride, but less than 60% DLR to metoclopramide (Reglan®), nemonapride (Emilace®), and zacopride. Antipsychotic, antidepressant, and antianxiety drugs from other chemical classes (chlorpromazine, quetiapine, risperidone, and mianserin) produced 35-55% amisulpride lever responding. Lastly, less than 35% DLR occurred for clozapine, olanzapine, aripiprazole imipramine, chlordiazepoxide, and bupropion. CONCLUSIONS: (RS)-Amisulpride generalized to some, but not all benzamide derivatives, and it failed to generalize to any other antipsychotic, antidepressant, or antianxiety drugs tested. Interestingly, the (R)-isomer shared very strong stimulus properties with (RS)-amisulpride. This finding was in contrast to findings from Donahue et al. (Eur J Pharmacol 734:15-22, 2014), which found that the (R)-isomer did not share very strong stimulus properties when the (S)-isomer was the training drug.

(S)-amisulpride as a discriminative stimulus in C57BL/6 mice and its comparison to the stimulus effects of typical and atypical antipsychotics.

Amisulpride, a substituted benzamide derivative, exerts atypical antipsychotic and antidepressant clinical effects and its (S)-stereoisomer is thought to underlie these actions. In the present study, male C57BL/6 mice were trained to discriminate (S)-amisulpride (10mg/kg, s.c.) from vehicle in a two-lever drug discrimination task for food reward. The (S)-amisulpride stimulus was rapidly acquired and was shown to be dose-related, time dependent (effective between 30 and 120min) and stereoselective: (S)-amisulpride (ED50=1.77mg/kg; 4.2µmol/kg) was about three times more potent than rac-amisulpride (ED50=4.94mg/kg; 13.4µmol/kg) and ten times more potent than (R)-amisulpride (ED50=15.84mg/kg; 42.9µmol/kg). In tests of stimulus generalization, the (S)-amisulpride stimulus generalized completely to sulpiride (ED50=12.67mg/kg; 37.1µmol/kg), a benzamide analog that also is purported to be an atypical antipsychotic, but did not fully generalize to the typical antipsychotic drug haloperidol (maximum of 45% drug-lever responding) nor to the atypical antipsychotic drugs clozapine (partial substitution of 65% drug-lever responding) or aripiprazole (~30% drug-lever responding). These results demonstrated that (S)-amisulpride appears to exert a unique discriminative stimulus effect that is similar to other benzamides, but which differs from other structural classes of antipsychotic drugs.