Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist
British Journal of PharmacologyPublished 1 February 2000Open access
Henri Doods, Gerhard Hallermayer, Dongmei Wu, Michael Entzeroth, K Rudolf, Wolfhard Engel
Citations468
SJR quartileQ1
SJR score2.34
SNIP1.51
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TL;DR
In an in vivo model, BIBN4096BS in doses between 1 and 30 μg kg−1 (i.v.) inhibited the effects of CGRP, released by stimulation of the trigeminal ganglion, on facial blood flow in marmoset monkeys, and it was concluded that BIBn40 96BS is a potent and selective CGRp antagonist.
Abstract
Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators known. This peptide is increased during migraine attacks and has been implicated in the pathogenesis of migraine headache. Here we report on the first small molecule selective CGRP antagonist: BIBN4096BS. In vitro, this compound is extremely potent at primate CGRP receptors exhibiting an affinity (Ki) for human CGRP receptors of 14.4 +/- 6.3 (n = 4) pM. In an in vivo model, BIBN4096BS in doses between 1 and 30 micrograms kg-1 (i.v.) inhibited the effects of CGRP, released by stimulation of the trigeminal ganglion, on facial blood flow in marmoset monkeys. It is concluded that BIBN4096BS is a potent and selective CGRP antagonist.
Keywords
MedicineNeuroscience
Biochemical PharmacologyRelationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction
12,904 Citations1973Yung-Chi Cheng, William H. Prusoff
The analysis described shows K I does not equal I 50 when competitive inhibition kinetics apply; however, K I is equal to I 50 under conditions of either noncompetitive or uncompetitive kinetics.
NatureAlternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products
2,133 Citations1982Susan Amara, Vivian Jonas +3 more
A model in which developmental regulation of RNA processing is used to increase the diversity of neuroendocrine gene expression is proposed.
Annals of NeurologyVasoactive peptide release in the extracerebral circulation of humans during migraine headache
1,610 Citations1990Peter J. Goadsby, Lars Edvinsson +1 more
A substantial elevation of the calcitonin gene‐related peptide level in the external jugular but not the cubital fossa blood was seen in both classic and common migraine, and may have importance in the pathophysiology of migraine.
Annals of NeurologyThe trigeminovascular system and migraine: Studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats
1,162 Citations1993Peter J. Goadsby, Lars Edvinsson
These data characterize some aspects of the cerebrovascular physiology of the trigeminovascular system and demonstrate important interactions between this system and the effective antimigraine agents sumatriptan and dihydroergotamine and that such interactions can be represented in animal models.
Annals of NeurologyThe neurobiology of vascular head pain
912 Citations1984Michael A. Moskowitz
The relationship of trigeminovascular fibers to the pathogenesis of vascular head pain sheds light on possible mechanisms of migraine and other central nervous system conditions associated with headache and inflammation.
Annals of NeurologyRelease of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system
870 Citations1988Peter J. Goadsby, Lars Edvinsson +1 more
The observation of elevation of substance P—like and CGRP‐like immunoreactivity after activation of the nociceptive afferent system of the head provides new insights into a putative role of peptides in the pathophysiology of migraine and cluster headache, and suggests new areas of possible therapeutic intervention.
American Journal of Physiology-Endocrinology and MetabolismCalcitonin gene-related peptide receptor antagonist human CGRP-(8-37)
363 Citations1989T. Chiba, Akinori Yamaguchi +7 more
Human calcitonin gene-related peptide fragment hCGRP-(8-37) appears to be a useful tool for determining whether the action of CGRP as well as that of CT is mediated via specific C GRP receptors or CT receptors.
Journal of Biological ChemistryA cDNA Encoding the Calcitonin Gene-related Peptide Type 1 Receptor
336 Citations1996Nambi Aiyar, Kinneret Rand +5 more
The cloning of a complementary DNA (cDNA) encoding a human CGRP receptor, which shares significant peptide sequence homology with the human calcitonin receptor, a member of the G-protein-coupled receptor superfamily, is reported here.
CephalalgiaVasoactive Peptide Levels in The Plasma of Young Migraine Patients With and Without Aura Assessed Both Interictally and Ictally
261 Citations1995Virgilio Gallai, Paola Sarchielli +6 more
The data suggest, although indirectly, that CGRP and NKA could be involved in the pathogenesis of migraine attacks in juvenile migraine patients.
British Journal of Pharmacology and ChemotherapypA<sub>x</sub> AND COMPETITIVE DRUG ANTAGONISM
245 Citations1949H. O. Schild
Guarino and Bovet evolve a new formula for the quantitative relations of antagonistic drugs whereby pA would be dependent on the concentration of active drug in competitive antagonism.
PubMedNeurovascular and molecular mechanisms in migraine headaches.
229 Citations1993M A Moskowitz, Robert Macfarlane
This chapter will review the consequences of trigeminovascular activation to pain and meningeal inflammation, and will summarize emerging molecular and pharmacological data suggesting that ergot alkaloids and sumatriptan alleviate pain primarily via activation of pre-junctional 5-HT1 heteroreceptors residing on primary afferent trigeminvascular fibers.
Headache The Journal of Head and Face PainNeural Processing of Craniovascular Pain: A Synthesis of the Central Structures Involved in Migraine
157 Citations1991Peter J. Goadsby, Alessandro S. Zagami +1 more
General Pharmacology The Vascular SystemCalcitonin gene-related peptide: Vasoactive effects and potential therapeutic role
96 Citations1996Susan D. Brain, H. Cambridge
CGRP is a potent and long-lasting vasodilator; its possible role in disease, and the therapeutic potential of CGRP receptor agonists and antagonists is discussed.
Molecular NeurobiologyCentral nervous system binding sites for calcitonin and calcitonin gene-related peptide
86 Citations1991Patrick M. Sexton
The present article reviews the biochemical and morphological characteristics of central CT and CGRP binding, sites and identifies a binding site with high-affinity binding for both peptides that has a restricted pattern of distribution.
Brain ResearchTrigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide
82 Citations1995Katherine J. Escott, David T. Beattie +2 more
Results suggest that CGRP is the major neuropeptide involved in the vasodilator response to trigeminal ganglion stimulation in rat facial skin, and clarification of the mechanisms involved may aid the development of drugs that target the trigeminovascular system during migraine headache.
Journal of Medicinal ChemistryFrom Micromolar to Nanomolar Affinity: A Systematic Approach To Identify the Binding Site of CGRP at the Human Calcitonin Gene-Related Peptide 1 Receptor
63 Citations1998Beate Rist, Michael Entzeroth +1 more
A series of ligands with multiple amino acid replacements in order to optimize the exchange at each position yielded to a series of high affinity ligands, including [D31,P34,F35] CGRP 27-37 which exhibits a 100-fold increased affinity compared to the unmodified segment.
Elsevier eBooksBIBP 3226, a potent and selective neuropeptide Y Y1-receptor antagonist. Structure-activity studies and localization of the human Y1 receptor binding site
19 Citations1997K Rudolf, Wolfgang Eberlein +5 more
It is found that BIBP 3226 reduced the pressor response induced by cold stress and normalized the cardiovascular changes and that that NPY and Y1 receptors play a significant role in the regulation of vascular tone during stress.