2. Academic Validation
  3. Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX

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

  • Eur J Pharmacol. 2018 Jun 15;829:85-92. doi: 10.1016/j.ejphar.2018.04.007.
Majid Sheykhzade 1,  Bahareh Abdolalizadeh 2,  Cassandra Koole 3,  Darryl Scott Pickering 1,  Karin Dreisig 4,  Sara Ellinor Johansson 4,  Balsam Kadri Abboud 2,  Rasmus Dreier 5,  Jais Oliver Berg 6,  Jørgen Lykke Jeppesen 7,  Patrick M Sexton 3,  Lars Edvinsson 4,  Denise Wootten 3,  Anette Sams 8
Affiliations

Affiliations

  • 1 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
  • 2 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark; Department of Clinical Experimental Research, Glostrup Research Institute, Glostrup University Hospital, Nordre Ringvej 69, DK-2600 Glostrup, Denmark.
  • 3 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia.
  • 4 Department of Clinical Experimental Research, Glostrup Research Institute, Glostrup University Hospital, Nordre Ringvej 69, DK-2600 Glostrup, Denmark.
  • 5 Department of Medicine, Amager Hvidovre Hospital Glostrup, Valdemar Hansens Vej 1-23, DK-2600 Glostrup, Denmark; Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet Glostrup, University of Copenhagen, Valdemar Hansens Vej 1-23, DK-2600 Glostrup, Denmark.
  • 6 Department of Plastic Surgery V, Herlev and Gentofte Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
  • 7 Department of Medicine, Amager Hvidovre Hospital Glostrup, Valdemar Hansens Vej 1-23, DK-2600 Glostrup, Denmark.
  • 8 Department of Clinical Experimental Research, Glostrup Research Institute, Glostrup University Hospital, Nordre Ringvej 69, DK-2600 Glostrup, Denmark. Electronic address: [email protected].
PMID: 29653090 DOI: 10.1016/j.ejphar.2018.04.007
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.

Keywords

CGRP; CGRP receptor; CGRP receptor antagonist; Human artery; Rat mesenteric artery.

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