title: Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies.
abstract: The 5-HT(2A)-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-HT(2A)-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-HT(2A)-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-HT(2A) 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.
authors.affiliation: Department of Psychiatry, Case Western Reserve University Medical School, Cleveland, OH 44106-4935, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Davies
authors.forename: V
authors.initials: V
authors.lastname: Setola
authors.forename: R T
authors.initials: RT
authors.lastname: Strachan
authors.forename: D J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: E
authors.initials: E
authors.lastname: Salay
authors.forename: S J
authors.initials: SJ
authors.lastname: Hufeisen
authors.forename: B L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002460:Cell Line; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D020641:Polymorphism, Single Nucleotide; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis / Q000235:genetics*; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists