A role for sigma binding in the antipsychotic profile of BMY 14802?
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.
Taylor
D P
DP
CNS Biology, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Wallingford, CT 06492-7660.
Eison
M S
MS
Moon
S L
SL
Schlemmer
R F
RF
Shukla
U A
UA
VanderMaelen
C P
CP
Yocca
F D
FD
Gallant
D J
DJ
Behling
S H
SH
Boissard
C G
CG
D000818:Animals; D001665:Binding Sites; D001923:Brain Chemistry / Q000187:drug effects; D006801:Humans; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D017480:Receptors, sigma / Q000187:drug effects* / Q000378:metabolism
D011619:Psychotropic Drugs; D011743:Pyrimidines; D017480:Receptors, sigma; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol