Cipralisant Explained

Cipralisant (GT-2331, tentative trade name Perceptin) is an extremely potent histamine H₃ receptor ligand originally developed by Gliatech.^[1] Cipralisant was initially classified as a selective H₃ antagonist,^[2] but newer research (2005) suggests also agonist properties, i.e., functional selectivity.

The relatively recent cloning of human H₃ receptor, as well as the discovery of its constitutive activity provided the ability to better assess the activity of H₃ receptor ligands. Consequently, cipralisant was reassessed as an H₃ receptor agonist in human and rat recombinant systems, showing functional selectivity and stimulating one type of G-protein coupled pathway while failing to activate other intracellular pathways.^[3]

Gliatech filed for bankruptcy in 2002, and its intellectual property was inherited by Merck. The development of cipralisant seems to have been suspended since 2003 but research is ongoing, and recently it has been shown that it is the (1S,2S)-enantiomer which is the biologically active one.^[4]

Notes and References

1. Ito S, Yoshimoto R, Miyamoto Y, Mitobe Y, Nakamura T, Ishihara A, MacNeil DJ, Kanatani A, Tokita S . 6 . Detailed pharmacological characterization of GT-2331 for the rat histamine H3 receptor . European Journal of Pharmacology . 529 . 1–3 . 40–46 . January 2006 . 16316645 . 10.1016/j.ejphar.2005.10.066 .
2. Tedford CE, Hoffmann M, Seyedi N, Maruyama R, Levi R, Yates SL, Ali SM, Phillips JG . 6 . High antagonist potency of GT-2227 and GT-2331, new histamine H3 receptor antagonists, in two functional models . European Journal of Pharmacology . 351 . 3 . 307–311 . June 1998 . 9721022 . 10.1016/S0014-2999(98)00396-3 . free .
3. Krueger KM, Witte DG, Ireland-Denny L, Miller TR, Baranowski JL, Buckner S, Milicic I, Esbenshade TA, Hancock AA . 6 . G protein-dependent pharmacology of histamine H3 receptor ligands: evidence for heterogeneous active state receptor conformations . The Journal of Pharmacology and Experimental Therapeutics . 314 . 1 . 271–281 . July 2005 . 15821027 . 10.1124/jpet.104.078865 . 20470970 .
4. Liu H, Kerdesky FA, Black LA, Fitzgerald M, Henry R, Esbenshade TA, Hancock AA, Bennani YL . 6 . An efficient multigram synthesis of the potent histamine H3 antagonist GT-2331 and the reassessment of the absolute configuration . The Journal of Organic Chemistry . 69 . 1 . 192–194 . January 2004 . 14703397 . 10.1021/jo035264t .