Selective Partial Agonism of Vasopressin 1a Receptors In Vitro by OCE-205
Glenn Croston1, Edward E. Cable1, Jeannine Toy1, Hiroe Tariga1, Regent Laporte1, Geoff Harris1, Stan Bukofzer2★★ Corresponding author
- 1Ferring Research Institute, San Diego, California, USA.
- 2Ocelot Bio Inc., San Diego, California, USA.
CORRESPONDENCE
Stan Bukofzer
Ferring Research Institute, San Diego, California, USA.
Received: 01-03-2023; Revised: 11-04-2023; Accepted: 12-04-2023.
Volume 14, Issue 1 · pp. 54–61 · PUBLISHED 2023 · DOI: 10.1177/0976500X231175220
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ABSTRACT
Objective: To test the selectivity and degree of functional agonism of Ocelot Bio’s dual agonist/antagonist molecule, OCE-205, at the vasopressin 1a receptor (V1aR). Methods: Cells expressing human (h) or rat V1a, V1b, V2, or oxytocin receptors (OTR) were incubated with varying concentrations of OCE-205 or with arginine vasopressin (AVP), and responses were measured with fluorescence or reporter gene assays. In addition, human resistance arteries were exposed to increasing concentrations of OCE-205, and the resulting contractility was measured. Results: The mean efficacy of OCE-205 at hV1aR was 39% of the maximal possible effect (MPE), with a mean EC50 of 0.71 nM. Above 1 nM OCE-205, the percent maximal possible effect (%MPE) plateaued. The EC50 was much higher at hV1bR (134 nM), hV2R (420 nM), and OTR (6.9 nM), indicating selectivity for hV1aR. Results at rat receptors were similar. OCE-205 produced 40.0% of maximal depolarization-induced contraction, demonstrating functional partial agonism. Conclusion: The dual agonist/antagonist structure of OCE-205 thus allows it to act as a highly selective partial agonist at vasopressin V1aR at therapeutically relevant concentrations.
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Croston, G., Cable, E. E., Toy, J., Tariga, H., Laporte, R., Harris, G., & Bukofzer, S. (2023). Selective Partial Agonism of Vasopressin 1a Receptors In Vitro by OCE-205. Journal of Pharmacology and Pharmacotherapeutics, 14(1), 54–61. https://doi.org/10.1177/0976500X231175220