Ruben van Drie (Rotterdam/ NL), Deirdre Boucherie (Rotterdam/ NL), Tessa de Vries (Rotterdam/ NL), A.H. Jan Danser (Rotterdam/ NL), Antoinette Maassen van den Brink (Rotterdam/ NL)
Abstract text (incl. figure legends and references)
Objectives
We aim to perform an in-depth pharmacological characterization of the potency of several gepants in porcine vasculature, in comparison with the potency in human blood vessels.
Methods
Distal coronary artery segments from 6 swine, obtained from the local slaughterhouse, were isolated and mounted in Mulvany myographs for isometric contraction measurements. Concentration response curves to human α-CGRP (10-10 – 3*10-6 M) were constructed in the absence or presence of increasing concentrations of olcegepant, rimegepant, zavegepant and telcagepant. The potency of the antagonists was determined by calculating pKb values. Results were compared to these obtained earlier in human isolated distal coronary arteries.
Results
Our results on olcegepant confirm our earlier observations (Gupta, et al. Eur J Pharmacol. 2006) of a lower potency in porcine coronary artery compared to human coronary artery (pKb 7.59±0.27 vs 9.13±0.17 respectively at 100 nM olcegepant). Preliminary results on rimegepant point to a similar difference in potency, as exemplified by the pKb values (100 nM: 6.35±0.04 vs 8.71±0.16, 1 μM: 6.35±0.04 vs 8.43±0.25 respectively) (Mulder, et al. Ann Neurol. 2020). Similarly, preliminary results on zavegepant again show a lower potency in porcine coronary arteries compared to human coronary artery (unpublished data) (pKb 100nM: 7.00±0.54 vs 9.91±0.15 respectively). For telcagepant an insufficient number of experiments was performed at the time of submission of the abstract.
Conclusions
Our initial analyses suggest that the difference in potency between porcine and human vasculature is similar for different gepants. Knowledge on this difference in potency between species, combined with molecular information about the structure of the CGRP receptor and the antagonists, provides information on the implications of the potency of gepants for translational research in experimental animals.