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

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Abstract

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 (pEC50 = 8.3) and 5-HT4 receptor-mediated relaxation of the rat esophagus (pEC50 = 7.9) and contraction of the guinea pig colon (pEC50 = 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 μM, had no effect on human ether-à-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.

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Abbreviations

DMEM:

Dulbecco’s Modified Eagles Medium

HEK-293:

Human embryonic kidney 293

IBS:

Irritable bowel syndrome

LMMP:

longitudinal muscle/myenteric plexus

SMP:

Submucous plexus

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Acknowledgements

The authors would like to thank Shanti Amagasu, Jeremy Hembrador, and Christa Peterson for electrophysiology support.

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  1. Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA

    J. A. M. Smith, D. T. Beattie, D. Marquess, J.-P. Shaw, R. G. Vickery & P. P. A. Humphrey

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  1. J. A. M. Smith
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  2. D. T. Beattie
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  3. D. Marquess
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  4. J.-P. Shaw
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  5. R. G. Vickery
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  6. P. P. A. Humphrey
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Correspondence to J. A. M. Smith.

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Smith, J.A.M., Beattie, D.T., Marquess, D. et al. The in vitro pharmacological profile of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity. Naunyn-Schmied Arch Pharmacol 378, 125–137 (2008). https://doi.org/10.1007/s00210-008-0282-y

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