The in vitro pharmacological profile of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity

The in vitro pharmacological profile of TD-5108, a novel, selective 5-HT4 receptor agonist, was compared to that of clinically efficacious gastroprokinetic 5-HT4 receptor agonists. TD-5108 produced an elevation of cyclic adenosine monophosphate in human embryonic kidney 293 cells expressing the human recombinant 5-HT4(c) (h5-HT4(c)) receptor (pEC(50) = 8.3) and 5-HT4 receptor-mediated relaxation of the rat esophagus (pEC(50) = 7.9) and contraction of the guinea pig colon (pEC(50) = 7.9). In all in vitro assays, TD-5108 was a high intrinsic activity agonist, unlike tegaserod, mosapride, and cisapride which, in the majority of test systems, had lower intrinsic activity. TD-5108 had high affinity (pK(i) = 7.7) and selectivity (>= 25-fold) for h5-HT4(c) receptors over other biogenic amine receptors. TD-5108 was > 500-fold selective over other 5-HT receptors (including h5-HT2B and h5-HT3A) and, at 3 mu M, had no effect on human ether-a-go-go-related gene K+ channels. In conclusion, TD-5108 is a selective 5-HT4 receptor agonist in vitro. The high intrinsic activity and preferential binding of TD-5108 to 5-HT4 over other 5-HT receptors may result in an improved clinical profile for the treatment of gastrointestinal disorders of reduced motility.