Binding Affinity, Selectivity, and Pharmacokinetics of the Oxytocin Receptor Antagonist L-368,899 in the Coyote (Canis latrans)

Authors

Sara M. Freeman, Utah State UniversityFollow
J. Leon Catrow, University of Utah
James Eric Cox, University of Utah
Alexandra Turano, Utah State University
McKenna A. Rich, Utah State University
Hillary P. Ihrig, Utah State University
Naveena Poudyal, Utah State University
Cheng-Wei Tom Chang, Utah State University
Eric M. Gese, United States Department of Agriculture, Wildlife Services, National Wildlife Research Center, Predator Research Facility, Millville, UtahFollow
Julie K. Young, United States Department of Agriculture, Wildlife Services, National Wildlife Research Center, Predator Research Facility, Millville, UtahFollow
Aaron L. Olsen, Utah State University

Document Type

Article

Date of this Version

2024

Citation

Comparative Medicine (February 2024) 74(1): 3-11

doi: 10.30802/AALAS-CM-23-000044

Comments

United States government work

Abstract

L-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that purpose was limited, L-368,899 is now one of the most commonly used drugs in animal research for the selective blockade of neural OXTR after peripheral delivery. A growing number of rodent and primate studies have used L-368,899 to evaluate whether certain behaviors are oxytocin dependent. These studies have improved our understanding of oxytocin’s function in the brains of rodents and monkeys, but very little work has been done in other mammals, and only a single paper in macaques has provided any evidence that L-368,899 can be detected in the CNS after peripheral delivery. The current study sought to extend those findings in a novel species: coyotes (Canis latrans). Coyotes are ubiquitous North American canids that form long-term monogamous pair-bonds. Although monogamy is rare in rodents and primates, all wild canid species studied to date exhibit social monogamy. Coyotes are therefore an excellent model organism for the study of oxytocin and social bonds. Our goal was to determine whether L-368,899 is a viable candidate for future use in behavioral studies in coyotes. We used captive coyotes at the USDA National Wildlife Research Center’s Predator Research Facility to evaluate the pharmacokinetics of L-368,899 in blood and CSF during a 90-min time course after intramuscular injection. We then characterized the binding affinity and selectivity of L-368,899 to coyote OXTR and the structurally similar vasopressin 1a receptor. We found that L-368,899 peaked in CSF at 15 to 30 min after intramuscular injection and slowly accumulated in blood. L-368,899 was 40 times more selective for OXTR than vasopressin 1a receptors and bound to the coyote OXTR with an affinity of 12 nM. These features of L-368,899 support its utility in future studies to probe the oxytocin system of coyotes.

Abbreviations and Acronyms: AVP, arginine vasopressin; AVPR1a, vasopressin 1a receptor; LVA, linearized vasopressin antagonist; MRM, multiple reaction monitoring; NWRC, National Wildlife Research Center; OBD, optical binding values; OVTA, ornithine vasotocin analog; OXT, oxytocin; OXTR, oxytocin receptor; PTFE, polytetrafluoroethylene