Cipralisant

GT‐2331 [(+)‐1] is one of the most potent members of a class of chiral drug substances used to regulate the synthesis and release of histamine by the histamine H3 receptor, and as such, is an important biomarker for pharmaceutical companies conducting research in this field. In addition to overall structural features, the bioactivity of this molecule has also been found to be highly dependent on absolute stereochemistry, making the reliable assignment of this property a necessity. X‐ray diffraction studies have provided conflicting data, leaving its three‐dimensional structure uncertain. In view of this, its absolute configuration was investigated by vibrational circular dichroism. Results from this study provided independent assignment of this important molecule as the (1S,2S)‐enantiomer. Chirality, 2007. © 2007 Wiley‐Liss, Inc.

A‐349821 is a selective histamine H3receptor antagonist/inverse agonist. Herein, binding of the novel non‐imidazole H3receptor radioligand [3H]A‐349821 to membranes expressing native or recombinant H3receptors from rat or human sources was characterized and compared with the binding of the agonist [3H]N‐α‐methylhistamine ([3H]NαMH).[3H]A‐349821 bound with high affinity and specificity to an apparent single class of saturable sites and recognized human H3receptors with 10‐fold higher affinity compared to rat H3receptors. [3H]A‐349821 detected larger populations of receptors compared to [3H]NαMH.Displacement of [3H]A‐349821 binding by H3receptor antagonists/inverse agonists was monophasic, suggesting recognition of a single binding site, while that of H3receptor agonists was biphasic, suggesting recognition of both high‐ and low‐affinity H3receptor sites.pKivalues of high‐affinity binding sites for H3receptor competitors utilizing [3H]A‐349821 were highly correlated with pKivalues obtained with [3H]NαMH, consistent with labelling of H3receptors by [3H]A‐349821.Unlike assays utilizing [3H]NαMH, addition of GDP had no effect on saturation parameters measured with [3H]A‐349821, while displacement of [3H]A‐349821 binding by the H3receptor agonist histamine was sensitive to GDP.In conclusion, [3H]A‐349821 labels interconvertible high‐ and low‐affinity states of the H3receptor, and displays improved selectivity over imidazole‐containing H3receptor antagonist radioligands. [3H]A‐349821 competition studies showed significant differences in the proportions and potencies of high‐ and low‐affinity sites across species, providing new information about the fundamental pharmacological nature of H3receptors.British Journal of Pharmacology(2006)148, 657–670. doi:10.1038/sj.bjp.0706752