igmesine and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol

Sigma ligands display antisecretory activity against various secretagogues, suggesting antidiarrhoeal properties. In this study, we evaluated: (i) the antidiarrhoeal effect of JO 2871, a high affinity sigma ligand, in three models of toxigenic diarrhoea in mice; and (ii) the site and mechanism of action of this compound.. Faeces were collected after toxin or vehicle administration in male DBA2 or NMRI mice. Diarrhoea was determined by cumulative stool weight (mg) over a 120 minute period. Diarrhoea was induced by intravenous administration of Salmonella enteriditis lipopolysaccharide (LPS), or oral administration of Escherichia coli heat stable (E coli-sta) or Clostridium difficile toxins. Two sigma ligands, igmesine and JO 2871, were administered either orally or intravenously, 60 and 30 minutes before the toxins, respectively. JO 2871 was also given orally 30 minutes after E coli-sta. In addition, JO 2871 was administered intracerebroventricularly five minutes before LPS and E coli-sta. BMY 14802 (1000 microg/kg orally), a sigma receptor antagonist, or cyclosomatostatin (CSS 1 microg/kg intravenously), a somatostatin antagonist, were given five minutes prior to JO 2871 in LPS, E coli-sta, and C difficile toxin treated mice. Gastric emptying and intestinal transit were evaluated after oral JO 2871 and BMY 14802 and intravenous CSS.. Stool weight measured 120 minutes after administration of the toxins was significantly increased. Oral JO 2871 and igmesine dose dependently inhibited toxigenic diarrhoea in all models. ED(50) values obtained using JO 2871 (1-20 microg/kg) were more than 40 times lower than those obtained with igmesine. Oral JO 2871 given after E coli-sta also inhibited diarrhoea in a dose dependent manner (ED(50) 50 microg/kg). Both sigma ligands were active by the intravenous route on LPS and E coli-sta induced stool weight increases. JO 2871 administered intracerebroventricularly failed to block this effect at any dose tested. Both BMY 14802 and CSS reversed the antidiarrhoeal effect of oral JO 2871. JO 2871, BMY 14802, and CSS did not affect transit parameters.. JO 2871 exerts a potent oral antidiarrhoeal effect, acting peripherally through sigma sites and somatostatin release.

Topics: Animals; Antidiarrheals; Bacterial Toxins; Cinnamates; Cyclopropanes; Defecation; Diarrhea; Dose-Response Relationship, Drug; Ligands; Male; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Pentazocine; Peptides, Cyclic; Pyrimidines; Receptors, sigma

A beneficial effect of sigma (sigma) agonists was previously described on several pharmacological models of learning impairments. We examined this effect in senescence-accelerated mice (SAM), which has been developed as a murine model of aging and cognitive dysfunction. SAMP8/Ta (P8, senescence-prone substrain), 10-12 months of age, showed significant impairments in mnemonic capacities, as compared to age-matched SAMR1/Ta controls (R1, senescence-resistant substrain). Tests included open-field behavior, spontaneous alternation performances in the Y-maze, step-down passive avoidance and place learning after repetitive training in a water-maze. Pretreatment with the sigma agonists JO-1784 (igmesine) or PRE-084, at 0.1-3 mg/kg, s.c., significantly improved spontaneous alternation and passive avoidance performances in P8. JO-1784 or PRE-084, at 1 mg/kg, also improved place learning in the water-maze, and retention, in term of escape latency. The implication of sigma sites was indicated by the lack of significant effect of JO-1783, the inactive enantiomer of JO-1784, and by the ability of BMY-14802 (5 mg/kg, i.p.) to antagonize the effects on passive avoidance of JO-1784 (0.5 mg/kg) or PRE-084 (1 mg/kg). Subchronic treatments with JO-1784 (0.5 mg/kg/day) or PRE-084 (1 mg/kg/day) during 10 days, allowed a significant improvement of learning during training in the water-maze, but retention was not significantly ameliorated. These results confirmed the interest of the SAM substrains as an experimental model for senile memory impairment and showed that sigma agonists could improve the quality of learning, although they seem less effective on long-term memory retrieval upon chronic administration.

Topics: Aging; Animals; Anti-Anxiety Agents; Antipsychotic Agents; Avoidance Learning; Cinnamates; Cyclopropanes; Learning; Maze Learning; Memory; Mice; Mice, Neurologic Mutants; Morpholines; Motor Activity; Phenazocine; Pyrimidines; Receptors, sigma

In an in vivo electrophysiological paradigm, we have shown in the companion paper that neuropeptide Y (NPY) potentiates N-methyl-D-aspartate (NMDA)-induced neuronal activation via a non-Y1, non-Y2, non-Y3 receptor subtype, in the rat CA3 dorsal hippocampus. Because sigma ligands have also been shown to potentiate NMDA-induced activation and because NPY and peptide YY have been reported to have high affinity for sigma binding sites, the present study was carried out to assess the possibility that the modulation of the NMDA response by NPY might be mediated by a sigma receptor. In the same electrophysiological paradigm, low doses of haloperidol and alpha-(4-fluorophenyl)-4-(5-fluoro-2- pyrimidinyl)-1-piperazine butanol, two antagonists of sigma receptors, reversed the potentiation of the NMDA response induced by NPY, [Leu31, Pro34]NPY or NPY13-36 and blocked the suppressant effect of desamido-NPY on the NMDA response. In contrast, spiperone, which has low affinity for sigma sites, was ineffective in suppressing NPY, as well as desamido-NPY-induced modulation of the NMDA response. In our model, peptide YY, which acts as a NPY antagonist by suppressing the potentiation of the NMDA response induced by NPY, also antagonized the potentiation of the NMDA response induced by the administration of low doses of di(2-tolyl)guanidine and (+)N-cyclopropyl-methyl-N-,methyl-1,4- diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride, two high-affinity sigma agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cinnamates; Cyclopropanes; Drug Synergism; Guanidines; Haloperidol; Hippocampus; Male; N-Methylaspartate; Neuropeptide Y; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Receptors, sigma; Spiperone

1. The central interactions between the sigma ligand, JO 1784, [(+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3- en-1-ylamine hydrochloride], or neuropeptide Y (NPY) and corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion were investigated in rats anaesthetized with urethane. Drugs were injected intracisternally (i.c.) or into specific hypothalamic nuclei. Gastric acid secretion was measured by the flushed technique under basal and pentagastrin (10 micrograms kg-1 h-1, i.v.) stimulated conditions. 2. Intracisternal injection of CRF (10 micrograms), bombesin (0.1 microgram) and human recombinant interleukin-1 beta (hIL-1 beta, 0.1 microgram) inhibited gastric acid response to pentagastrin by 72%, 56% and 62%, respectively. NPY (0.5 microgram) or JO 1784 (0.5 microgram) injected i.c. did not alter acid secretion but completely prevented the inhibitory effect of CRF. The antagonistic effect of NPY and JO 1784 against CRF was dose-related (0.01-0.5 microgram) and peptide-specific since NPY and JO 1784 did not alter the antisecretory action of bombesin or hIL-1 beta. 3. The putative sigma receptor antagonist, BMY 14802, (1 mg kg-1, s.c.) did not influence pentagastrin-stimulated acid secretion nor CRF-induced inhibition of gastric acid secretion; however, BMY 14802 administered s.c. 20 min before JO 1784 or NPY, abolished the antagonistic effect of both JO 1784 and NPY. 4. CRF (3 micrograms) microinjected into the hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) inhibited pentagastrin-stimulated gastric acid secretion by 61% and 51%; NPY (0.03 micrograms) or JO 1784 (0.03 micrograms) microinjected into the PVN had no effect by themselves but blocked CRF antisecretory action.There were more VPBs (220 +/- 75), a higher incidence of VT (60%) and more episodes of VT (11.5 +/- 6.0 compared to 0.7 +/- 0.3 episodes in the preconditioned dogs not given L-NAME); none of the animals survived reperfusion (incidence of VF 100%). The improvement in the severity of the degree of inhomogeneity which resulted from preconditioning was abolished by L-NAME administration.5. L-NAME itself elevated blood pressure (from 96 +/- 5 mmHg diastolic to 119 +/- 7 mmHg), reduced heart rate (from 155 +/- 7 to 144 +/- 4 beats min-') but did not change LVEDP, LVdP/dt,,,,, coronary blood flow, ST-segment elevation or the degree of inhomogeneity of conduction. When given 10 min before the prolonged coronary artery occlusion in

Topics: Animals; Bombesin; Cinnamates; Cisterna Magna; Corticotropin-Releasing Hormone; Cyclopropanes; Dose-Response Relationship, Drug; Gastric Acid; Humans; Interleukin-1; Male; Microinjections; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pentagastrin; Psychotropic Drugs; Pyrimidines; Rats; Rats, Sprague-Dawley