2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and igmesine

There is evidence for the existence of two classes of sigma binding sites, termed "site 1" and "site 2", that are distinct from opioid and PCP receptors. Sigma receptor ligands may be useful in the treatment of schizophrenia, since they improve not only positive but also negative symptoms with little extrapyramidal side effects in animal models. In addition, recent experiments have demonstrated that sigma receptor ligands attenuate the motor suppression and colonic motor disturbances seen under mentally stressful situations, stimulate the central cholinergic function thereby ameliorating impairment of learning and memory, and protect cerebral neurons against cerebral ischemic insult. The present review describes the neuropharmacological effects of sigma receptor ligands, especially anxiolytic (anti-stress) effects, ameliorating effects on impairment of learning and memory, and neuroprotective effects.

Topics: Animals; Antipsychotic Agents; Anxiety; Brain Ischemia; Cinnamates; Cyclopropanes; Humans; Learning Disabilities; Memory Disorders; Phenazocine; Phencyclidine; Receptors, sigma

The sigma1 receptor is a unique intracellular receptor whose activation results in an efficient modulation of several neurotransmitter responses. Its role as a target for the rapid nongenomic effects of neuro(active)steroids and the age-related diminutions in steroid levels suggested that targeting the sigma1 receptor might allow alleviation of age-related neuronal dysfunctions. We examined here the expression and behavioral efficacy of sigma1 receptors in the senescence-accelerated (SAM) mouse model. The sigma1 receptor mRNA expression was measured by using comparative RT-PCR in the olfactory bulb, hippocampus, hypothalamus, cortex, or cerebellum of senescence-prone SAMP/8 and senescence-resistant SAMR/1 control animals. No difference was observed between substrains in 6-, 9-, and 12-month-old (m.o.) mice. The sigma1 protein expression was analyzed by using immunohistochemical techniques. Labeling was intense in the olfactory bulb, hippocampus, hypothalamus, and midbrain of both SAMR/1 and SAMP/8 mice, and the distribution appeared unchanged in 6-, 9-, and 12-m.o. animals. The receptor's in vivo availability was examined by using in vivo [3H](+)-SKF-10,047 binding. No age-related difference was observed in the olfactory bulb, hippocampus, hypothalamus, cortex, cerebellum, and brainstem of 6- or 12-m.o. SAMR/1 or SAMP/8 mice. The antidepressant efficacy of the selective agonist igmesine was examined in the forced-swimming test. The compound decreased significantly the immobility duration at 60 mg/kg in 6- and 12-m.o. SAMR/1 and in 6-m.o. SAMP/8 mice. In 12-m.o. SAMP/8 mice, the drug efficacy was facilitated; a significant effect was measured at 30 mg/kg. Decreased neurosteroid levels, particularly of progesterone, were seen in 12-m.o. SAMP/8 mice that might explain the enhanced efficacy of igmesine. Preserved sigma1 receptor expression and enhanced behavioral efficacy of sigma1 agonists were measured in SAM animals, confirming the therapeutic opportunities for selective ligands against age-related mood disorders.

Topics: Age Factors; Aging; Animals; Antidepressive Agents; Antipsychotic Agents; Behavior, Animal; Blotting, Northern; Brain; Cinnamates; Cyclopropanes; Dehydroepiandrosterone; Dose-Response Relationship, Drug; Gene Expression Regulation; Immunohistochemistry; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Phenazocine; Pregnenolone; Progesterone; Radioligand Assay; Receptors, sigma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Tritium

Treatment of depressive symptoms in patients suffering from neurodegenerative disorders remains a challenging issue, since few available antidepressants present an adequate efficacy during pathological aging. Previous reports suggested that selective sigma(1) receptor agonists might constitute putative candidates. We here examined the pharmacological efficacy of igmesine and (+)-SKF-10,047 and the sigma(1) receptor-related neuroactive steroid dehydroepiandrosterone sulfate, in rats infused intracerebroventricularly during 14 days with the beta-amyloid-(1-40) protein and then submitted to the conditioned fear stress test. Igmesine and (+)-SKF-10,047 significantly reduced the stress-induced motor suppression at 30 and 6 mg/kg, respectively, in beta-amyloid-(40-1)-treated control rats. Active doses were decreased, to 10 and 3 mg/kg, respectively, in beta-amyloid-(1-40)-treated animals. The dehydroepiandrosterone sulfate effect was also facilitated, both in dose (10 vs. 30 mg/kg) and intensity, in beta-amyloid-(1-40)-treated rats. Neurosteroid levels were measured in several brain structures after beta-amyloid infusion, in basal and stress conditions. Progesterone levels, both under basal and stress-induced conditions, were decreased in the hippocampus and cortex of beta-amyloid-(1-40)-treated rats. The levels in pregnenolone, dehydroepiandrosterone and their sulfate esters appeared less affected by the beta-amyloid infusion. The sigma(1) receptor agonist efficacy is known to be inversely correlated to brain progesterone levels, synthesized mainly by neurons that are mainly affected by the beta-amyloid toxicity. The present study suggests that sigma(1) receptor agonists, due to their enhanced efficacy in a nontransgenic animal model, may alleviate Alzheimer's disease-associated depressive symptoms.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antidepressive Agents; Brain; Cinnamates; Conditioning, Psychological; Cyclopropanes; Dehydroepiandrosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Fear; Injections, Intraventricular; Male; Peptide Fragments; Phenazocine; Pregnenolone; Progesterone; Rats; Rats, Wistar; Receptors, sigma; Sigma-1 Receptor; Stress, Psychological

The sigma(1) (sigma(1)) receptor exerts a potent neuromodulatory role in the brain with relevant consequences in memory processes, response to stress, depression and pharmacodependence. Its precise endogenous ligand is not yet identified but the sigma(1) receptor appears to be one target for the nongenomic rapid effects of neuroactive steroids in the brain. The aim of the present study was to establish whether differences in sigma(1) receptor-mediated behaviours could be observed among mouse strains, in relation with differences in either sigma(1) receptor expression or steroid levels. The sigma(1)-receptor immunohistochemical distribution appeared similar between Swiss and C57BL/6 strains in all the brain structures examined. The levels of in vivo [(3)H](+)-SKF-10 047 binding to sigma(1) receptors were lower in Swiss than in C57BL/6. Adrenalectomy/castration significantly increased [(3)H](+)-SKF-10 047 binding only in Swiss. The behavioural efficacy of the selective sigma( 1) agonists igmesine and PRE-084 -- reversion of the scopolamine-induced amnesia in the passive avoidance test; diminution of the immobility duration in the forced swimming test -- were significantly higher in C57BL/6 than in Swiss. Steroid levels were measured in the brain in basal conditions and after stress. C57BL/6 mice presented in both conditions, the lowest progesterone levels, this steroid acting as an endogenous sigma(1) antagonist. Collectively, the results suggested that strain differences in neuroactive steroid and particularly, progesterone, biosynthesis and sensitivity may contribute to the differential behavioural efficacy of sigma(1)-receptor ligands. Noteworthy, these observations are coherent with strain differences observed in the intensity of cocaine-induced reward properties, known to critically involve the sigma(1) receptor.

Topics: Animals; Antidepressive Agents; Antipsychotic Agents; Behavior, Animal; Binding Sites; Brain; Brain Chemistry; Cinnamates; Cocaine; Conditioning, Psychological; Cyclopropanes; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Morpholines; Neurons; Nootropic Agents; Phenazocine; Radioligand Assay; Receptors, sigma; Sigma-1 Receptor; Steroids

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

The effects of putative sigma ligands and two neuropeptides on intestinal ion transport were evaluated in isolated sheets of whole mouse jejunum mounted in Ussing flux chambers. Serosal administration of neuropeptide Y (NPY), peptide YY (PYY), (+)-N-cyclopropylmethyl-N-methyl-1,4- diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO 1784), di(ortho-tolyl)guanidine (DTG) and (+)- or (-)-N-allyl-normetazocine (NANM) produced concentration-related decreases in short-circuit current (Isc) without changes in tissue conductance. Although NPY and PYY were active in nanomolar concentrations, JO 1784, DTG and (+)- and (-)-NANM were active in micromolar concentrations; the rank order of potency in inhibiting Isc was PYY > NPY >> JO 1784 = (-)-N- cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride > DTG > (+)-NANM = (-)-NANM. Serosal application of tetrodotoxin effectively blocked the decrease in Isc associated with all of the ligands tested. The activity of the serosally applied ligands was blocked by prior application of chlorisondamine, a ganglionic blocker. The effects of JO 1784 and NPY were evaluated using antagonists of several receptor types. Although application of serosal haloperidol had no effect alone up to concentrations of 1 microM, this compound produced a rightward displacement in both the NPY and JO 1784 concentration-effect curves. In contrast, sulpiride, SCH-23390, naloxone, yohimbine and prazosin failed to antagonize the effects of NPY or JO 1784.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cinnamates; Cyclopropanes; Guanidines; In Vitro Techniques; Ion Transport; Jejunum; Male; Mice; Mice, Inbred ICR; Neuropeptide Y; Peptide YY; Peptides; Phenazocine; Receptors, sigma

JO 1784 ((+)-N-Cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride), has been recently described as a selective ligand for the sigma receptor with an IC50 of 39 +/- 8 nM28. In the present study the effects of JO 1784 on experimental induced amnesia were investigated using one trial passive avoidance task in rats. Amnesia was produced by injecting scopolamine (1 mg/kg i.p.) 30 min before the second session (T2) on day 2 of the passive avoidance task. The anti-amnesic effect of JO 1784 was compared with other typical and atypical psychotropic drugs which interact at the sigma and or the phencyclidine site. JO 1784 was studied at 5 doses; 0.0625, 0.25, 1.0, 4.0 and 16.0 mg/kg i.p. ((+)-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine ((+)-3-PPP). Rimcazole, (+)-N-allylnormetazocine ((+)-NANM), 1,3-di(2-tolyl) guanidine (DTG) were studied at 4 doses; 0.25, 1.0, 4.0 and 8.0 mg/kg i.p. All drugs were administered 60 min before the test (T2) on day 2 i.e. 30 min before scopolamine. Piracetam (1000 mg/kg p.o.) administered in the same test conditions was used as a reference compound in each experiment. Of the drugs investigated JO 1784 (0.25, 1.0, 4.0 and 16.0 mg/kg i.p.), (+)-3-PPP (0.25, 1.0 and 4.0 mg/kg i.p.), DTG (1.0, 4.0 and 8.0 mg/kg) and piracetam significantly reversed scopolamine induced amnesia on day 3 (T3). At the lower dose, JO 1784 (0.0625 mg/kg) failed to reverse the amnesic effects of scopolamine on day 3. These results suggest that JO 1784 the selective sigma ligand, may be beneficial in amnesic status.

Topics: Amnesia; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Carbazoles; Cinnamates; Cyclopropanes; Dopamine Agents; Dose-Response Relationship, Drug; Guanidines; Ligands; Male; Phenazocine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Scopolamine

JO 1784 ((+)-cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene) is a potent ligand for (+)-[3H]SKF 10,047 (2'-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan) binding sites in rat brain membrane preparations with an IC50 of 39 +/- 8 nM, which is comparable to that of haloperidol. The stereoisomer of JO 1784 is ten fold less potent. When administered to mice i.p. or p.o. JO 1784 displaced (+)-[3H]SKF 10,047 (5 muCi i.v.) from its sites in the brain with ID50 values of 1.2 and 3.5 mg kg-1, respectively. The high selectivity of JO 1784 for the sigma-binding site was assessed by its lack of significant affinity for more than 20 other sites including those for phencyclidine.

Topics: Animals; Brain Chemistry; Cinnamates; Cyclopropanes; In Vitro Techniques; Male; Mice; Phenazocine; Phencyclidine; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta

The influence of central vs. peripheral administration of sigma ligands (dl- and l-N-allylnormetazocine, 1-3-di-o-tolylguanidine, (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene and phencyclidine on colonic motility was investigated in fasted and fed dogs equipped with strain-guage transducers implanted on proximal and transverse colon. When injected intravenously at a dose of 0.25 mg/kg just before feeding, dl- or d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene (but not phencyclidine) enhanced the colonic motor response to a meal by increasing the 0-4-hour motility indexes from 64.1%-159.3% in both the proximal and transverse colon but had no effect on colonic motility in fasted animals or animals injected intracerebroventricularly. The motor-stimulatory effects of d-N-allylnormetazocine (1 mg/kg), 1-3-di-o-tolylguanidine (0.25 mg/kg), and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene (1 mg/kg) were abolished after previous treatment with haloperidol (0.5 mg/kg, intravenous) but not after sulpiride (0.1 mg/kg) or (+) R-(+)-8-chloro-2,3,4,5-tetrahydro-3- methyl-5-phenyl-1-H-3-benzozepine-OH. Prazosin (0.1 mg/kg, intravenous) and 1-methyl-3-(2-indolyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one (0.01 mg/kg) also suppressed the enhancement of the colonic motor response to eating induced by d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+)cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene whereas naltrexone did not affect their effects. It is concluded that d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+)cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene stimulate the postprandial colonic motility in dogs by acting selectively on sigma receptors located peripherally and probably by affecting the release of cholecystokinin octapeptide through a central adrenergic mechanism.

Topics: Animals; Cinnamates; Colon; Cyclopropanes; Dogs; Drug Antagonism; Eating; Gastrointestinal Motility; Guanidines; Injections, Intravenous; Injections, Intraventricular; Phenazocine; Phencyclidine; Receptors, Opioid; Receptors, sigma; Stereoisomerism