Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX

Majid Sheykhzade, Bahareh Abdolalizadeh, Cassandra Koole, Darryl Scott Pickering, Karin Dreisig, Sara Ellinor Johansson, Balsam Kadri Abboud, Rasmus Dreier, Jais Oliver Berg, Jørgen Lykke Jeppesen, Patrick M. Sexton, Lars Edvinsson, Denise Wootten, Anette Sams

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Abstract

The main purpose of this study was to compare in vitro pharmacological properties of human αCGRP (CGRP) and a recently discovered metabolically stable CGRP analogue, SAX, in isolated rat and human artery segments. In rat, CGRP and SAX induced similar vasodilatory responses in isolated mesenteric artery with the potency of SAX being lower than that of CGRP (vasodilatory pEC50 8.2 ± 0.12 and 9.0 ± 0.11, respectively). A corresponding difference in receptor binding affinity of SAX and CGRP was determined in rat cerebral membranes (pKi 8.3 ± 0.19 and 9.3 ± 0.14, respectively). CGRP and SAX-induced vasodilation was antagonised with similar potencies by the CGRP receptor antagonist BIBN4096BS supporting a uniform receptor population for the agonists. In human tissue, SAX and CGRP induced similar pharmacological responses with different potencies in subcutaneous artery (vasodilatory pEC50 8.8 ± 0.18 and 9.5 ± 0.13, respectively) and human recombinant receptors (cAMP signalling pEC50 9.1 ± 0.16 and 10.2 ± 0.19). Like in the rat mesenteric artery, both SAX and CGRP-responses were inhibited by the CGRP receptor antagonist BIBN4096BS with similar antagonistic potencies. In conclusion, all pharmacological characteristics of SAX and CGRP in human and rat sources points towards action via a uniform BIBN4096BS sensitive receptor population with the potency of SAX being 5–10 fold lower than that of CGRP.

Original languageEnglish
Pages (from-to)85-92
Number of pages8
JournalEuropean Journal of Pharmacology
Volume829
DOIs
Publication statusPublished - 15 Jun 2018

Keywords

  • CGRP
  • CGRP receptor
  • CGRP receptor antagonist
  • Human artery
  • Rat mesenteric artery

Cite this

Sheykhzade, M., Abdolalizadeh, B., Koole, C., Pickering, D. S., Dreisig, K., Johansson, S. E., ... Sams, A. (2018). Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX. European Journal of Pharmacology, 829, 85-92. https://doi.org/10.1016/j.ejphar.2018.04.007