期刊
PHARMACOGENOMICS JOURNAL
卷 6, 期 1, 页码 42-51出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.tpj.6500342
关键词
5-HT2A; serotonin receptors; T25N; I197V; A447V; H452Y
资金
- NIMH NIH HHS [R01MH57635, K02MH01366] Funding Source: Medline
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH057635, K02MH001366] Funding Source: NIH RePORTER
The 5-HT2A-serotonin receptor is a major molecular target for most atypical antipsychotic drugs as well as most hallucinogens, which can exacerbate psychotic symptoms. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT2A-serotonin receptor could explain inter-individual variability in atypical antipsychotic and agonist drug response. We examined the in vitro pharmacology of four non-synonymous SNPs, which give rise to T25N, I197V, A447V, and H452Y variant 5-HT2A-serotonin receptors. Our data indicate that these non-synonymous SNPs exert statistically significant, although modest, effects on the affinity and functional effects of several currently approved atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone). Also, the 5-HT2A receptor SNPs slightly altered the potency and relative efficacy of a small number of selected agonists (2,5-dimethoxy-4-iodoamphetamine, tryptamine, 5-hydroxytryptamine, m-chlorophenylpiperazine, and 5-methoxy-N, N-dimethyltryptamine). In all, our results show that the in vitro pharmacological effects of the SNPs are drug specific.
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