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

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The purpose of this study was to compare in vitro pharmacological properties of human αCGRP (CGRP) and SAX, a metabolically stable CGRP analog, in isolated rat and human artery segments (vasoactivity), in recombinant human CGRP receptors (cAMP accumulation), and in native rat receptors (receptor binding).
Vasodilatory potencies (pEC50) of SAX and CGRP in isolated rat mesenteric artery were 8.2 ± 0.12 and 9.0 ± 0.11 and the CGRP receptor antagonist BIBN4096BS competitively inhibited the vasodilatory effects of SAX and CGRP with potencies (pA2) of 7.6 ± 0.13 and 8.0 ± 0.16. mRNAs encoding CGRP receptors (CLR and RAMP1) were expressed in the artery. In rat cerebral membranes, binding affinities (pKi) of SAX and CGRP were 8.3 ± 0.19 and 9.3 ± 0.14.
In human subcutaneous artery, SAX and CGRP induced vasodilation (pEC50 8.8 ± 0.18 and 9.5 ± 0.13), while pEC50s for cAMP production by human recombinant receptors were 9.1 ± 0.16 and 10.2 ± 0.19. Here, pA2 values of BIBN4096BS were 10.5 ± 0.24 and 11.1 ± 0.32. The presence of albumin caused a selective 10-fold reduction in potency and binding affinity of SAX.
In conclusion, SAX and CGRP act on a uniform BIBN4096BS sensitive receptor population in our experiments and the potency of SAX is 5-10 fold lower than that of CGRP.
Original languageEnglish
JournalEuropean Journal of Pharmacology
Pages (from-to)85-92
Publication statusPublished - 2018

ID: 193173387