Linked Life Data

16959943

Source:http://linkedlifedata.com/resource/pubmed/id/16959943

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2006-11-19
pubmed:abstractText
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 CGRP(1) receptors are CL/RAMP1, whereas BIBN4096BS-insensitive AM receptors are CL/RAMP2 or CL/RAMP3 (AM(1) and AM(2), 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 approximately 150-fold less sensitive to BIBN4096BS antagonism than CGRP(1) receptors. In contrast, AMY(3(a)) [CT((a))/RAMP3] or AM(2) 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 CGRP(1) 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 AM(2) and AMY(3(a)) receptors. It is interesting that a selective reduction in AM potency was observed at E74W AM(2) 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 CGRP(1) 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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
70
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1984-91
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
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.
pubmed:affiliation
School of Biological Sciences, University of Auckland, Symonds Street, Auckland, New Zealand.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't