CGRP; further research on non-peptide antagonists

[Guest guest]

Hi All,

Along with NO inhibitors, CGRP antagonists (inhibitors) may have a

siginificant theraputic effect (potentially reducing or eliminating

redness, burning and flushing) when applied topically. There are

already dozens of peer-reviewed medical studies showing how CGRP is

intimately involved in cutaneous blood vessel dilation (and also pain

response) and how blocking CGRP reduces blood flow and redness

(usually using cutaneous injections of the antagonist CGRP(8-37)). I

have been following for some time the development of a non-peptide

antagonist BIBN4096BS; according to the doctors and researchers I

have been communicating with, this has much more *potential* as a

topical medication.

There is a new study now available on this, which I post below. For

anyone interested on the whole CGRP connection, try medline. There

is a vast amount of information out there, particularly in the papers

by Dr. Brain of King's College London (her URL has some of her

most recent papers:

http://www.kcl.ac.uk/depsta/biomedical/cardio/brain.html).

Along with Nitric Oxide, CGRP is one of the key " mediators " of blood

vessel dilation.

.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

cmd=Retrieve&db=PubMed&list_uids=11955527&dopt=Abstract

Neuropharmacology 2002 Mar;42(4):568-76 Books, LinkOut

Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in

blocking CGRP-induced dilations in human and bovine cerebral

arteries: potential implications in acute migraine treatment.

Moreno MJ, Abounader R, Hebert E, Doods H, Hamel E.

Laboratory of Cerebrovascular Research, Montreal Neurological

Institute, McGill University, 3801 University Street, QC, H3A 2B4,

Montreal, Canada

Calcitonin gene-related peptide (CGRP) is a potent vasodilator in

brain vessels and it has been implicated in the pathogenesis of

migraine headache. Blocking post-junctional CGRP receptors, mediators

of trigeminal-induced vasodilation, has been suggested as a potential

antimigraine strategy. In this study, we tested the ability of a new

non-peptide CGRP receptor antagonist, BIBN4096BS, to inhibit the CGRP-

induced dilation in human and/or bovine brain vessels and compared it

to that of the antagonist alpha-CGRP(8-37). BIBN4096BS and alpha-CGRP

(8-37) both blocked the alpha-CGRP-induced dilation in bovine middle

artery segments with respective potency (pK( values) of 6.3 and

7.8. In human pial vessels, BIBN4096BS was particularly potent. When

tested at 10(-14)-10(-9) M concentrations, it induced a rightward

shift in the alpha-CGRP concentration-response curve and yielded a

biphasic Schild plot suggesting interaction with more than one

receptor population, as was also indicated by the significant best

fit of the alpha-CGRP-induced dilation in human brain vessels with a

two receptor site interaction. Schild plot analysis in the linear

portion of the BIBN4096BS inhibition curve revealed interaction with

one high affinity site (pA(2) value approximately 14). In bovine

vessels, both alpha-CGRP(8-37) and BIBN4096BS concentration-

dependently reversed a pre-established CGRP-induced dilation (

approximately 59 and 85%, respectively), BIBN4096BS being

approximately tenfold more potent than alpha-CGRP(8-37) (respective

pIC(50) values of 7.5 and 6.75). In human middle cerebral and middle

meningeal arteries, BIBN4096BS reversed the alpha-CGRP-induced

dilation (>/=70%) by interaction with two different receptor

populations: it exhibited a high affinity for one population (pIC(50)

value approximately 13) and a lower affinity for the other (pIC(50)

value approximately 8). The present data demonstrate that BIBN4096BS

is a very potent antagonist that could, depending on its

bioavailability and in vivo affinity, be of potential benefit in the

acute treatment of migraine headache by blocking and/or reversing the

CGRP-mediated dilation of intracranial vessels induced by activation

of trigeminovascular afferents.

[Guest guest]

, thanks for this. I'll check it out, and report back anything

interesting/relevant.

Marjorie

>

> Along with NO inhibitors, CGRP antagonists (inhibitors) may have a

> siginificant theraputic effect (potentially reducing or eliminating

> redness, burning and flushing) when applied topically. There are

> already dozens of peer-reviewed medical studies showing how CGRP is

> intimately involved in cutaneous blood vessel dilation (and also

pain

> response) and how blocking CGRP reduces blood flow and redness

> (usually using cutaneous injections of the antagonist CGRP(8-37)).

I

> have been following for some time the development of a non-peptide

> antagonist BIBN4096BS; according to the doctors and researchers I

> have been communicating with, this has much more *potential* as a

> topical medication.

>

> There is a new study now available on this, which I post below.

For

> anyone interested on the whole CGRP connection, try medline. There

> is a vast amount of information out there, particularly in the

papers

> by Dr. Brain of King's College London (her URL has some of

her

> most recent papers:

> http://www.kcl.ac.uk/depsta/biomedical/cardio/brain.html).

>

> Along with Nitric Oxide, CGRP is one of the key " mediators " of

blood

> vessel dilation.

>

> .

>

>

> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

> cmd=Retrieve&db=PubMed&list_uids=11955527&dopt=Abstract

>

> Neuropharmacology 2002 Mar;42(4):568-76 Books, LinkOut

>

>

> Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in

> blocking CGRP-induced dilations in human and bovine cerebral

> arteries: potential implications in acute migraine treatment.

>

> Moreno MJ, Abounader R, Hebert E, Doods H, Hamel E.

>

> Laboratory of Cerebrovascular Research, Montreal Neurological

> Institute, McGill University, 3801 University Street, QC, H3A 2B4,

> Montreal, Canada

>

> Calcitonin gene-related peptide (CGRP) is a potent vasodilator in

> brain vessels and it has been implicated in the pathogenesis of

> migraine headache. Blocking post-junctional CGRP receptors,

mediators

> of trigeminal-induced vasodilation, has been suggested as a

potential

> antimigraine strategy. In this study, we tested the ability of a

new

> non-peptide CGRP receptor antagonist, BIBN4096BS, to inhibit the

CGRP-

> induced dilation in human and/or bovine brain vessels and compared

it

> to that of the antagonist alpha-CGRP(8-37). BIBN4096BS and alpha-

CGRP

> (8-37) both blocked the alpha-CGRP-induced dilation in bovine

middle

> artery segments with respective potency (pK( values) of 6.3 and

> 7.8. In human pial vessels, BIBN4096BS was particularly potent.

When

> tested at 10(-14)-10(-9) M concentrations, it induced a rightward

> shift in the alpha-CGRP concentration-response curve and yielded a

> biphasic Schild plot suggesting interaction with more than one

> receptor population, as was also indicated by the significant best

> fit of the alpha-CGRP-induced dilation in human brain vessels with

a

> two receptor site interaction. Schild plot analysis in the linear

> portion of the BIBN4096BS inhibition curve revealed interaction

with

> one high affinity site (pA(2) value approximately 14). In bovine

> vessels, both alpha-CGRP(8-37) and BIBN4096BS concentration-

> dependently reversed a pre-established CGRP-induced dilation (

> approximately 59 and 85%, respectively), BIBN4096BS being

> approximately tenfold more potent than alpha-CGRP(8-37) (respective

> pIC(50) values of 7.5 and 6.75). In human middle cerebral and

middle

> meningeal arteries, BIBN4096BS reversed the alpha-CGRP-induced

> dilation (>/=70%) by interaction with two different receptor

> populations: it exhibited a high affinity for one population (pIC

(50)

> value approximately 13) and a lower affinity for the other (pIC(50)

> value approximately 8). The present data demonstrate that

BIBN4096BS

> is a very potent antagonist that could, depending on its

> bioavailability and in vivo affinity, be of potential benefit in

the

> acute treatment of migraine headache by blocking and/or reversing

the

> CGRP-mediated dilation of intracranial vessels induced by

activation

> of trigeminovascular afferents.

[Guest guest]

, thanks for this. I'll check it out, and report back anything

interesting/relevant.

Marjorie

>

> Along with NO inhibitors, CGRP antagonists (inhibitors) may have a

> siginificant theraputic effect (potentially reducing or eliminating

> redness, burning and flushing) when applied topically. There are

> already dozens of peer-reviewed medical studies showing how CGRP is

> intimately involved in cutaneous blood vessel dilation (and also

pain

> response) and how blocking CGRP reduces blood flow and redness

> (usually using cutaneous injections of the antagonist CGRP(8-37)).

I

> have been following for some time the development of a non-peptide

> antagonist BIBN4096BS; according to the doctors and researchers I

> have been communicating with, this has much more *potential* as a

> topical medication.

>

> There is a new study now available on this, which I post below.

For

> anyone interested on the whole CGRP connection, try medline. There

> is a vast amount of information out there, particularly in the

papers

> by Dr. Brain of King's College London (her URL has some of

her

> most recent papers:

> http://www.kcl.ac.uk/depsta/biomedical/cardio/brain.html).

>

> Along with Nitric Oxide, CGRP is one of the key " mediators " of

blood

> vessel dilation.

>

> .

>

>

> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

> cmd=Retrieve&db=PubMed&list_uids=11955527&dopt=Abstract

>

> Neuropharmacology 2002 Mar;42(4):568-76 Books, LinkOut

>

>

> Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in

> blocking CGRP-induced dilations in human and bovine cerebral

> arteries: potential implications in acute migraine treatment.

>

> Moreno MJ, Abounader R, Hebert E, Doods H, Hamel E.

>

> Laboratory of Cerebrovascular Research, Montreal Neurological

> Institute, McGill University, 3801 University Street, QC, H3A 2B4,

> Montreal, Canada

>

> Calcitonin gene-related peptide (CGRP) is a potent vasodilator in

> brain vessels and it has been implicated in the pathogenesis of

> migraine headache. Blocking post-junctional CGRP receptors,

mediators

> of trigeminal-induced vasodilation, has been suggested as a

potential

> antimigraine strategy. In this study, we tested the ability of a

new

> non-peptide CGRP receptor antagonist, BIBN4096BS, to inhibit the

CGRP-

> induced dilation in human and/or bovine brain vessels and compared

it

> to that of the antagonist alpha-CGRP(8-37). BIBN4096BS and alpha-

CGRP

> (8-37) both blocked the alpha-CGRP-induced dilation in bovine

middle

> artery segments with respective potency (pK( values) of 6.3 and

> 7.8. In human pial vessels, BIBN4096BS was particularly potent.

When

> tested at 10(-14)-10(-9) M concentrations, it induced a rightward

> shift in the alpha-CGRP concentration-response curve and yielded a

> biphasic Schild plot suggesting interaction with more than one

> receptor population, as was also indicated by the significant best

> fit of the alpha-CGRP-induced dilation in human brain vessels with

a

> two receptor site interaction. Schild plot analysis in the linear

> portion of the BIBN4096BS inhibition curve revealed interaction

with

> one high affinity site (pA(2) value approximately 14). In bovine

> vessels, both alpha-CGRP(8-37) and BIBN4096BS concentration-

> dependently reversed a pre-established CGRP-induced dilation (

> approximately 59 and 85%, respectively), BIBN4096BS being

> approximately tenfold more potent than alpha-CGRP(8-37) (respective

> pIC(50) values of 7.5 and 6.75). In human middle cerebral and

middle

> meningeal arteries, BIBN4096BS reversed the alpha-CGRP-induced

> dilation (>/=70%) by interaction with two different receptor

> populations: it exhibited a high affinity for one population (pIC

(50)

> value approximately 13) and a lower affinity for the other (pIC(50)

> value approximately 8). The present data demonstrate that

BIBN4096BS

> is a very potent antagonist that could, depending on its

> bioavailability and in vivo affinity, be of potential benefit in

the

> acute treatment of migraine headache by blocking and/or reversing

the

> CGRP-mediated dilation of intracranial vessels induced by

activation

> of trigeminovascular afferents.