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Determinants of 1-Piperidinecarboxamide, N-[2-[[5-Amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) Affinity for Calcitonin Gene-Related Peptide and Amylin Receptors—The Role of Receptor Activity Modifying Protein 1

School of Biological Sciences, University of Auckland, Symonds Street, Auckland, New Zealand (D.L.H.); and Drug Discovery Biology Laboratory, Department of Pharmacology, Monash University, Victoria, Australia (P.M.S., A.C., G.C.)

1-Piperidinecarboxamide, N-[2-[[5-amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS), a calcitonin gene-related peptide (CGRP) receptor antagonist, can alleviate the symptoms of migraine and is highly selective for CGRP over adrenomedullin (AM) receptors. These receptors are heterodimers of the calcitonin receptor-like receptor (CL) and receptor activity modifying proteins (RAMPs), with the pharmacological properties determined by the RAMP subunit. BIBN4096BS-sensitive CGRP₁ receptors are CL/RAMP1, whereas BIBN4096BS-insensitive AM receptors are CL/RAMP2 or CL/RAMP3 (AM₁ and AM₂, respectively), implicating RAMP1 in conferring BIB-N4096BS sensitivity. Because calcitonin receptors [CT_(a)] also interact with RAMP1 [AMY_1(a) receptors], BIBN4096BS could also have affinity for these receptors. To test this, receptors were transfected into COS-7 cells and agonist-stimulated cAMP levels measured in the presence and absence of antagonists. We found that AMY_1(a) receptors were 150-fold less sensitive to BIBN4096BS antagonism than CGRP₁ receptors. In contrast, AMY_3(a) [CT_(a)/RAMP3] or AM₂ receptors were not sensitive to BIBN4096BS antagonism. We investigated Trp74 in RAMP1, a residue implicated in the species selectivity of BIBN4096BS. BIBN4096BS affinity was reduced at AMY_1(a) and CGRP₁ receptors when this residue was mutated to lysine or alanine. The equivalent residue in RAMP3, Glu74, when mutated to tryptophan (E74W), induced BIBN4096BS sensitivity at AM₂ and AMY_3(a) receptors. It is interesting that a selective reduction in AM potency was observed at E74W AM₂ receptors, implicating this residue in AM interactions with this receptor. These data support the importance of Trp74 in RAMP1 in the interaction of BIBN4096BS with CGRP₁ and AMY_1(a) receptors and identified Glu74 in RAMP3 as the first amino acid in RAMP important for agonist interactions with calcitonin-family receptors.

Received for publication June 14, 2006.

Accepted for publication September 6, 2006.

Address correspondence to: Dr. Patrick M. Sexton, Drug Discovery Biology Laboratory, Department of Pharmacology, Monash University, Victoria 3800, Australia. E-mail: patrick.sexton{at}med.monash.edu.au

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