CGRP receptors mediating CGRP-, adrenomedullin- and amylin-induced relaxation in porcine coronary arteries. Characterization with ‘Compound 1' (WO98/11128), a non-peptide antagonist

摘要: Calcitonin gene-related peptide (CGRP), amylin and adrenomedullin (AM) belong to the same family of peptides. Accumulating evidence indicate that calcitonin (CT) receptor, CT receptor-like receptor (CRLR) receptor-activity-modifying proteins (RAMPs) form basis all receptors in this peptides. Using reverse transcriptase–polymerase chain reaction presence mRNA sequences encoding CRLR, RAMP1 RAMP2 were demonstrated porcine left anterior descending (LAD) coronary arteries, whereas was not present. The partial shared 82–92% nucleotide identity with human sequences. The peptides αCGRP, βCGRP, AM induced relaxation pEC50 values 8.1, 6.7 6.1 M respectively. The antagonistic properties a novel non-peptide CGRP antagonist ‘Compound 1’ (WO98/11128), βCGRP8–37 proposed AM22–52 compared well-known CGRP1 αCGRP8–37. The αCGRP8–37 concentration-dependent (10−7–10−5 M) rightward shift both αCGRP βCGRP concentration-response curves. (10−6 M) had effect as (10−6 M), but less potent curves for amylin. Preincubation no significant effect. In conclusion, building blocks forming present LAD, those not. mediated vasorelaxation via receptors. No functional response detected receptor. British Journal Pharmacology (2001) 133, 1405–1413; doi:10.1038/sj.bjp.0704210