BMY 14802 hydrochloride

IC50: 112 nM for (+)-[3H]-3-PPP

The theoretical role of sigma receptors in psychosis has led to the discovery of selective sigma receptor ligands as potential antipsychotic agents. BMY 14802 is a sigma receptor ligand.

In vitro: BMY 14802 has its most potent binding at the sigma binding site, with some degree of serotonin subtype 1A and negligible dopamine receptor binding [1].

In vivo: BMY 14802 is atypical of standard neuroleptics in that it does not induce catalepsy in rats. In addition, it has been shown to have efficacy in animal models of psychosis [1].

Clinical trial: After 1 week of single-blind placebo treatment, 28 patients were treated with BMY 14802 (up to 3000 mg/day) for up to 4 weeks. However, there was no significant improvement in psychiatric symptoms. There were no changes in involuntary movements, as measured by the Abnormal Involuntary Movement Scale, or in extrapyramidal symptoms as measured by the Simpson-Angus Scale [1].

Reference:
[1] Gewirtz GR, Gorman JM, Volavka J, Macaluso J, Gribkoff G, Taylor DP, Borison R. BMY 14802, a sigma receptor ligand for the treatment of schizophrenia. Neuropsychopharmacology. 1994 Feb;10(1):37-40.

A role for sigma binding in the antipsychotic profile of BMY 14802?[Pubmed:8232511]

NIDA Res Monogr. 1993;133:125-57.

BMY 14802 was identified as a potential antipsychotic drug in traditional model systems, and this identification was confirmed in modern behavioral and electrophysiological systems. The drug appears to be atypical as an antipsychotic in its lack of activity in models predictive of the potential to produce extrapyramidal side effects and tardive dyskinesia. Indeed, this suggestion is corroborated by clinical findings to date. The atypical profile of BMY 14802 extends to its neurochemical actions and appears to find its basis in regionally selective, indirect modulation of the dopamine system. Furthermore, BMY 14802 exhibits interactions with sigma binding sites in vitro and in vivo, a notion supported by data from neurophysiological, behavioral, and biochemical investigations. BMY 14802 also appears to be neuroprotective in some model systems and may have utility in the treatment of stroke (Boissard et al. 1991). BMY 14802 appears to interact with 5-HT1A receptors, but this interaction does not seem to contribute significantly to the potential antipsychotic actions of the drug. Moreover, the formation of active metabolites of BMY 14802 does not appear to occur in animals or humans to an extent of physiological or behavioral relevance. If clinically efficacious, BMY 14802 may treat the symptoms of schizophrenia by a mechanism novel for antipsychotic drugs: regionally selective, indirect modulation of dopaminergic systems by specific interaction at sigma sites.

Further characterization of the effects of BMY 14802 on dopamine neuronal activity.[Pubmed:7908761]

Synapse. 1993 Dec;15(4):276-84.

Further evaluation of the effects of BMY 14802 on dopamine (DA) neuronal activity in the rat substantia nigra pars compacta (A9) was conducted with single-unit recording and microiontophoresis in anesthetized rats. Microiontophoretic administration of BMY 14802 (sigma, serotonin (5-HT)-1A and alpha-1 adrenoceptor ligand) had no effect on DA neurons. Microiontophoretic administration of (+)-3-PPP (weak D2 agonist with high affinity for sigma receptors) and quinpirole (D2/D3 agonist) inhibited A9 DA neuronal activity. Co-iontophoresis or i.v. pretreatment with BMY 14802 had no effect on the current-response curves for the effects of microiontophoretic (+)-3-PPP or quinpirole on A9 DA neurons. Co-iontophoretic administration of (-)-sulpiride, a selective D2 antagonist, blocked the inhibitory effects of microiontophoretic (+)-3-PPP. The effects of BMY 14802 (0.25-8 mg/kg, i.v.) on DA neurons (increased firing rate, increased burst-firing, reduced regularity of firing pattern) were not altered by acute brain hemitransection, but were blocked by pretreatment with NAN-190, an antagonist of 5-HT-1A and alpha-1 receptors. The alpha-1 receptor antagonist, prazosin, did not block these effects of BMY 14802. In conclusion, the effects of BMY 14802 on DA neuronal firing rate and firing pattern are indirect, perhaps due in part to the occupation of 5-HT-1A receptors.

Synthesis and biological characterization of alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol and analogues as potential atypical antipsychotic agents.[Pubmed:1361578]

J Med Chem. 1992 Nov 27;35(24):4516-25.

A series of 1-(pyrimidin-2-yl)piperazine derivatives were prepared and evaluated in receptor binding assays and in in vivo behavioral paradigms as potential atypical antipsychotic agents. Compound 16 (BMS 181100 (formerly BMY 14802)) emerged as the lead compound from within the series on the basis of its good activity and duration of action in the inhibition of both conditioned avoidance responding and apomorphine-induced stereotopy in the rat. Compound 16 not only failed to induce catalepsy in the rat but was quite effective in reversing the cataleptic effect of neuroleptic agents, thus indicating a low propensity for causing extrapyramidal side effects. In comparison to reference antipsychotic agents, 16 appeared to be less sedating and was relatively weaker in causing muscle incoordination. The compound was essentially inactive in binding to dopamine D2 receptors and its chronic administration to rats did not result in dopamine receptor supersensitivity. It exhibited modest to weak affinity for 5-HT1A and alpha 1 receptors but was found to be a fairly potent ligand for sigma binding sites (IC50 vs (+)-[3H]-3-PPP = 112 nM). Although the resolved enantiomers of racemic 16 did not show dramatic differences from racemate or from each other in most tests, the R(+) enantiomer was up to 11-fold more potent than its antipode in binding to sigma sites. Several studies have indicated that 16 may be a limbic-selective agent which may modulate dopaminergic activity by an indirect mechanism. The compound has been selected for clinical evaluation in the treatment of psychosis.