BMY 14802, a Sigma Receptor Ligand for the Treatment of Schizophrenia

Gewirtz, George; Gorman, Jack M.; Volavka, Jan; Macaluso, Joseph; Gribkoff, Greta; Taylor, Duncan P.; Borison, Richard L.

doi:10.1038/npp.1994.5

Cited by 61 publications

(40 citation statements)

References 5 publications

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“…In addition, a number of newer drugs with antipsychotic efficacy have been found to possess high affinity for the sigma binding site (34). However, not all attempts to demonstrate antipsychotic efficacy of sigma ligands have proven successful (20). Finally, there is some evidence for alterations in sigma receptors in schizophrenic patients; however, these changes were noted in medicated populations (47,48,69).…”

Section: Discussionmentioning

confidence: 85%

The Delayed Effects of DTG and MK-801 on Latent Inhibition in a Conditioned Taste-Aversion Paradigm

Turgeon¹,

Auerbach²,

Duncan-Smith³

et al. 2000

Pharmacology Biochemistry and Behavior

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. The delayed effects of DTG and MK-801 on latent inhibition in a conditioned taste-aversion paradigm. PHARMACOL BIOCHEM BEHAV 66 (3) 533-539, 2000.-The delayed effects of phencyclidine (PCP) have been shown to disrupt latent inhibition (LI) in a conditioned taste-aversion paradigm. In an attempt to understand the mechanism of this disruption, the delayed effects of the selective sigma receptor agonist 1,3-Di(2-tolyl)guanidine (DTG) and the selective NMDA receptor antagonist MK-801 on latent inhibition were assessed in the same paradigm. Water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE) for 30 min on 2 consecutive days. On the third day, animals were allowed access to sucrose and subsequently injected with lithium chloride. On the forth day, animals were allowed access to both sucrose and water. LI was assessed by comparing the percent sucrose consumed in PE and NPE groups on the fourth day. DTG (1.0, 5.0, or 10.0 mg/kg), MK-801 (0.5, 1.0, or 2.0 mg/kg), or vehicle was administered IP 20 h before preexposure (days 1 and 2) and conditioning (day 3). In vehicle-treated groups, PE animals consumed a significantly higher percent sucrose on the test day than NPE animals, indicating the presence of LI. DTG (10.0 mg/kg) and MK-801 (2.0 mg/kg) decreased the percent sucrose consumed by animals in the PE group to the level observed in the NPE group, indicating disrupted LI. However, this dose of MK-801 was found to produce a decrease in percent sucrose consumed in PE animals not treated with lithium chloride, indicating that the decrease observed in the LI paradigm could be due to MK-801-induced decrease in taste preference for sucrose rather than a disruption of LI. Lower doses of MK-801 that did not produce a decrease in taste preference for sucrose did not significantly disrupt LI. None of the doses of DTG tested altered taste preference for sucrose. These data suggest a role for sigma receptors in the previously observed PCP-induced disruption of LI. LATENT inhibition (LI) is the impaired acquisition of a conditioned response to a stimulus that has been previously presented without reinforcement (35). LI is thought to be a measure of an organism's capacity to ignore irrelevant stimuli, and has been demonstrated in a variety of species including humans (4,35,36). Disruption of LI has been observed in nonmedicated acute schizophrenics (4) as well as animals and humans treated with the psychotomimetic drug amphetamine (14,22,49,(64)(65)(66)(67). Medicated schizophrenic patients do not demonstrate disrupted LI (4,37). In addition, antipsychotic medications reverse amphetamine-induced disruption of LI in animals (49,68), and can enhance LI on their own (11,15). These observations suggest that the disruption of LI is a useful animal model for this specific attentional deficit seen in schizophrenia (12,15). Phencyclidine (PCP) is a drug that can produce a psychotomimetic effect in humans (3,28,38) as well as a number of behavioral and cognitive changes in animals...

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Section: Discussionmentioning

confidence: 85%

The Delayed Effects of DTG and MK-801 on Latent Inhibition in a Conditioned Taste-Aversion Paradigm

Turgeon¹,

Auerbach²,

Duncan-Smith³

et al. 2000

Pharmacology Biochemistry and Behavior

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“…Although this is consistent with earlier studies showing similar antagonism of amphetamine-induced behavior, it raises the question of whether the antidyskinetic effects of BMY-14802 could result from nonspecific motoric suppression. This seems unlikely, as earlier studies clearly demonstrate that σ antagonists lack sedative effects, both in preclinical studies with nondopaminergic stimulants [20] and in clinical trials in schizophrenia [21]. Another concern is that L-DOPA-induced rotation has sometimes been used as a marker for L-DOPA's therapeutic effects, and thus its reduction by BMY-14802 could indicate suppression of L-DOPA's therapeutic effects.…”

Section: Discussionmentioning

confidence: 90%

“…This also seems unlikely since BMY-14802 has been demonstrated to counteract dystonia induced in rodents by σ agonists, including haloperidol [13]. Similarly, no parkinsonian effects were observed in clinical trials of BMY-14802 in schizophrenia [21]. Studies are underway in our laboratory to evaluate the consequences of BMY-14802 on L-DOPA-mediated improvements of forelimb use.…”

Section: Discussionmentioning

confidence: 99%

Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias

Paquette¹,

Brudney

Putterman³

et al. 2008

NeuroReport

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Levodopa (L-DOPA) is the 'gold standard' to treat Parkinson's disease. Unfortunately, dyskinesias detract from its efficacy. Current dyskinesia treatments, including amantadine and dextromethorphan, are thought to work via N-methyl-D-aspartate (NMDA) antagonism, but this hypothesis has not been tested. The NMDA antagonists MK-801and HA-966 failed to suppress expression of dyskinesias in the 6-hydroxydopamine rat. Dyskinesias, however, were suppressed by the NMDA and sigma (σ)-1receptor ligand dextromethorphan and by the σ-1 antagonist BMY-14802. Antidyskinetic effects of dextromethorphan may be mediated via mechanisms other than NMDA, including the σ-1 receptor and other binding sites common to dextromethorphan and BMY-14802.

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“…Most of these studies implied that sigma-binding sites are plasmalemmal elements of the signal transduction cascade. Drugs reported to be selective sigma-ligands were evaluated as antipsychotics (23)(24)(25). Due to the lack of structural and functional information, the pharmacological significance of sigma-binding sites remains enigmatic.…”

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confidence: 99%

Purification, molecular cloning, and expression of the mammalian sigma1-binding site.

Hanner

Moebius

Flandorfer

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

837

781

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BMY 14802, a Sigma Receptor Ligand for the Treatment of Schizophrenia

Cited by 61 publications

References 5 publications

The Delayed Effects of DTG and MK-801 on Latent Inhibition in a Conditioned Taste-Aversion Paradigm

The Delayed Effects of DTG and MK-801 on Latent Inhibition in a Conditioned Taste-Aversion Paradigm

Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias

Purification, molecular cloning, and expression of the mammalian sigma1-binding site.

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