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VUF10166, a novel compound with differing activities at 5-HT?A and 5-HT?AB receptors.

ABSTRACT: The actions of a novel, potent 5-HT? receptor ligand, [2-chloro-(4-methylpiperazine-1-yl)quinoxaline (VUF10166)], were examined at heterologously expressed human 5-HT?A and 5-HT?AB receptors. VUF10166 displaced [³H]granisetron binding to 5-HT?A receptors expressed in human embryonic kidney cells with high affinity (K(i) = 0.04 nM) but was less potent at 5-HT?AB receptors (K(i) = 22 nM). Dissociation of [³H]granisetron in the presence of VUF10166 was best fit with a single time constant (t(1/2) = 53 min) at 5-HT?A receptors, but with two time constants (t(1/2) = 55 and 2.4 min) at 5-HT?AB receptors. Electrophysiological studies in oocytes revealed that VUF10166 inhibited 5-HT-induced responses at 5-HT?A receptors at nanomolar concentrations, but inhibition and recovery were too slow to determine an IC??. At 5-HT?AB receptors, inhibition and recovery were faster, yielding an IC?? of 40 nM. Cysteine substitutions in the complementary (-), but not the principal (+), face of the 5-HT?B subunit produced heteromeric receptors in which the actions of VUF10166 resembled those at homomeric receptors. At 5-HT?A receptors, VUF10166 at higher concentrations also behaved as a partial agonist (EC?? = 5.2 ?M; R(max) = 0.24) but did not elicit significant responses at 5-HT?AB receptors at ?100 ?M. Thus, we propose that VUF10166 binds to the common A+A- site of both receptor types and to a second A+B- modulatory site in the heteromeric receptor. The ability of VUF10166 to distinguish between 5-HT?A and 5-HT?AB receptors could help evaluate differences between these receptor types and has potential therapeutic value.

SUBMITTER: Thompson AJ

PROVIDER: S-EPMC3336813 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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VUF10166, a novel compound with differing activities at 5-HT₃A and 5-HT₃AB receptors.

Thompson A J AJ Verheij M H P MH de Esch I J P IJ Lummis S C R SC

The Journal of pharmacology and experimental therapeutics 20120203 2

The actions of a novel, potent 5-HT₃ receptor ligand, [2-chloro-(4-methylpiperazine-1-yl)quinoxaline (VUF10166)], were examined at heterologously expressed human 5-HT₃A and 5-HT₃AB receptors. VUF10166 displaced [³H]granisetron binding to 5-HT₃A receptors expressed in human embryonic kidney cells with high affinity (K(i) = 0.04 nM) but was less potent at 5-HT₃AB receptors (K(i) = 22 nM). Dissociation of [³H]granisetron in the presence of VUF10166 was best fit with a single time constant (t(1/2) = ...[more]

PMID: 22306960

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Project description:BackgroundCerebrotendinous xanthomatosis (CTX) is an autosomal-recessive lipid storage disorder caused by mutations in the CYP27A1 gene encoding the key enzyme in the bile acid synthesis, sterol 27-hydroxylase. Here, we report two Japanese CTX siblings with a novel compound heterozygous CYP27A1 mutation, showing different clinical phenotypes and responses to chenodeoxycholic acid (CDCA) therapy.Case presentationThe proband, a 32-year-old man, who had chronic diarrhea, bilateral cataracts, and xanthomas, demonstrated progressive neurological manifestations including ataxia, and spastic paraplegia during a 5-year follow-up period despite normalization of serum cholestanol after initiation of CDCA treatment. He also exhibited cognitive decline although improvement had been observed at the beginning of treatment. Follow-up brain magnetic resonance imaging (MRI) revealed pronounced progressive atrophy in the cerebellum, in addition to expanding hyperintense lesions in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives on T2-weighted images. In contrast, the two-year-younger sister of the proband presented with chronic diarrhea, cataracts, xanthomas, and intellectual disability but no other neurological symptoms at the time of diagnosis. CDCA treatment lead to improvement of cognitive function and there were no characteristic CTX-related MRI features during the follow-up period. The siblings shared a paternally inherited c.1420C > T mutation (p.Arg474Trp) and a maternally inherited novel c.1176_1177delGA mutation, predicting p.(Glu392Asp*20).ConclusionsOur cases suggest that early diagnosis and subsequent initiation of CDCA treatment are crucial before the appearance of characteristic MRI findings and severe neurological manifestations related to CTX. Further studies are required to elucidate mechanisms responsible for the clinical diversity of CTX and prognostic factors for long-term outcomes following initiation of CDCA treatment.

Dataset Information

VUF10166, a novel compound with differing activities at 5-HT?A and 5-HT?AB receptors.

Publications

VUF10166, a novel compound with differing activities at 5-HT₃A and 5-HT₃AB receptors.

Similar Datasets

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