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The in vitro pharmacological profile of TD-1211, a neutral opioid receptor antagonist

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Abstract

The clinical efficacy of opioid receptor antagonists for the treatment of opioid-induced constipation (OIC) is established. Peripherally selective antagonists are intended to provide OIC symptom relief without compromising the analgesic effects of centrally penetrant opioid agonists. We describe the in vitro profile of a novel opioid receptor antagonist, TD-1211, at recombinant (human μ and δ, and guinea pig κ) and rodent native opioid receptors. TD-1211 bound with high affinity to human recombinant μ and δ, and guinea pig κ receptors expressed in CHO-K1 cells (pK d = 9.7, 8.6, and 9.9, respectively). The in vitro receptor selectivity of TD-1211 (μ ≈ κ > δ) is similar to that for the peripherally-selective opioid receptor antagonist methylnaltrexone, but contrasts with the μ selectivity of alvimopan. Functionally, TD-1211 behaved as an antagonist at all three receptor types in both recombinant expression systems (pK b = 9.6, 8.8 and 9.5, at μ, δ, and κ, respectively) and rodent native tissue preparations (μ and κ pA2s = 10.1 and 8.8, respectively (guinea pig ileum), and δ pK b = 8.4 (hamster vas deferens)). TD-1211 displayed a high degree of selectivity for opioid receptors over a broad panel of cellular targets. These in vitro data justified investigation of the preclinical in vivo activity of TD-1211 (Armstrong et al., Naunyn-Schmiedeberg’s Arch Pharm, 2013).

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Abbreviations

OIC:

Opioid-induced constipation

GI:

Gastrointestinal

CNS:

Central nervous system

HEPES:

4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid

DMSO:

Dimethyl sulfoxide

DAMGO:

[d-Ala2, N-MePhe4, Gly-ol]enkephalin

DPDPE:

[d-Pen2,5]enkephalin

U69593:

N-Methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl] acetamide

EFS:

Electrical field stimulation

BSA:

Bovine serum albumin

CHO:

Chinese hamster ovary

IA:

Intrinsic activity

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Acknowledgments

The authors would like to thank Shanti Amagasu, Madhavi Ravindran, Courtney Gee, Ngoc Mai, Joey Yung, and Shana Johnson Rabidoux for technical support, and Uwe Klein for a thoughtful review of the manuscript.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA

    Pamela R. Tsuruda & Ross G. Vickery

  2. Department of Medicinal Chemistry, Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA

    Daniel D. Long

  3. Department of Pharmacology, Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA

    Scott R. Armstrong & David T. Beattie

Authors
  1. Pamela R. Tsuruda
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  2. Ross G. Vickery
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  3. Daniel D. Long
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Correspondence to Pamela R. Tsuruda.

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Fig. S1

Representative saturation binding of [3H]TD-1211 at human recombinant μ (a), human recombinant δ (b), or guinea pig recombinant κ receptors (c) (DOCX 40 kb)

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Tsuruda, P.R., Vickery, R.G., Long, D.D. et al. The in vitro pharmacological profile of TD-1211, a neutral opioid receptor antagonist. Naunyn-Schmiedeberg's Arch Pharmacol 386, 479–491 (2013). https://doi.org/10.1007/s00210-013-0850-7

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