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

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

doi:10.1016/j.ejphar.2018.04.007

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

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

Department of Clinical Medicine

8 Citations (Scopus)

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 language	English
Journal	European Journal of Pharmacology
Volume	829
Pages (from-to)	85-92
ISSN	0014-2999
DOIs	https://doi.org/10.1016/j.ejphar.2018.04.007
Publication status	Published - 15 Jun 2018

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10.1016/j.ejphar.2018.04.007

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Sheykhzade, M., Abdolalizadeh, B., Koole, C., Pickering, D. S., Dreisig, K., Johansson, S. E., Abboud, B. K., Dreier, R., Berg, J. O., Jeppesen, J. L., Sexton, P., Edvinsson, L., Wootten, D., & 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

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

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.",

author = "Majid Sheykhzade and Bahareh Abdolalizadeh and Cassandra Koole and Pickering, {Darryl S} and Karin Dreisig and Johansson, {Sara Ellinor} and Abboud, {Balsam Kadri} and Rasmus Dreier and Berg, {Jais Oliver} and Jeppesen, {J{\o}rgen Lykke} and Patrick Sexton and Lars Edvinsson and Denise Wootten and Anette Sams",

year = "2018",

month = jun,

day = "15",

doi = "10.1016/j.ejphar.2018.04.007",

language = "English",

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journal = "European Journal of Pharmacology",

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T1 - Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX

AU - Sheykhzade, Majid

AU - Abdolalizadeh, Bahareh

AU - Koole, Cassandra

AU - Pickering, Darryl S

AU - Dreisig, Karin

AU - Johansson, Sara Ellinor

AU - Abboud, Balsam Kadri

AU - Dreier, Rasmus

AU - Berg, Jais Oliver

AU - Jeppesen, Jørgen Lykke

AU - Sexton, Patrick

AU - Edvinsson, Lars

AU - Wootten, Denise

AU - Sams, Anette

PY - 2018/6/15

Y1 - 2018/6/15

N2 - 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.

AB - 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.

U2 - 10.1016/j.ejphar.2018.04.007

DO - 10.1016/j.ejphar.2018.04.007

M3 - Journal article

C2 - 29653090

SN - 0014-2999

VL - 829

SP - 85

EP - 92

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

ER -

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

Abstract

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