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A comparison of the pharmacological properties of guinea‐pig and human recombinant 5‐HT 4 receptors
Author(s) -
Vickery R G,
Mai N,
Kaufman E,
Beattie D T,
PulidoRios T,
O'Keefe M,
Humphrey P P A,
Smith J A M
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707154
Subject(s) - guinea pig , receptor , agonist , 5 ht4 receptor , myenteric plexus , pharmacology , biology , tegaserod , 5 ht receptor , serotonin , chemistry , medicine , endocrinology , biochemistry , immunology , immunohistochemistry , irritable bowel syndrome
Background and purpose: 5‐HT 4 receptor agonists are used therapeutically to treat disorders of reduced gastrointestinal motility. Since such compounds are evaluated in guinea‐pigs, we cloned, expressed and pharmacologically characterized the guinea‐pig 5‐HT 4 and human 5‐HT 4(b) splice variant, which share 95% homology. The functional properties of guinea‐pig 5‐HT 4(b) receptors were compared with native receptors in guinea‐pig colon. Experimental approach: Membrane radioligand binding and whole cell cAMP accumulation assays were used to determine the affinities, potencies and intrinsic activities (IA). Contraction of the guinea‐pig distal colon longitudinal muscle myenteric plexus preparation (LMMP) was monitored to evaluate functional activity. Key results: pK i values for guinea‐pig and human recombinant receptors, and guinea‐pig striatum 5‐HT 4 receptors, were in agreement, as were the potency and IA values for guinea‐pig and human 5‐HT 4 receptors expressed at a similar density (∼0.2 pmol mg −1 protein). Tegaserod was a potent ( pEC 50 =8.4 and 8.7, respectively), full agonist at both guinea‐pig and human 5‐HT 4 receptors. In contrast, in the LMMP preparation, tegaserod was a potent, partial agonist ( pEC 50 =8.2; IA=66%). Conclusions and implications: Close agreement between the pharmacological properties of guinea‐pig and human 5‐HT 4 receptors support the use of guinea‐pig model systems for the identification of 5‐HT 4 receptor therapeutics. However, the mechanisms underlying the different agonist properties of tegaserod in recombinant and isolated tissue preparations, and the extent to which these impact the clinical efficacy of tegaserod as a prokinetic agent, remain to be determined. British Journal of Pharmacology (2007) 150 , 782–791. doi: 10.1038/sj.bjp.0707154