Abstract
The blood-brain barrier permeabilities of the type-A cholecystokinin receptor antagonists devazepide and A-65186 (N(α)-3-quinolinoyl-D-Glu-N,N-dipentylamide) have been compared with those of the reference compounds iodoantipyrine, which readily penetrates the blood-brain barrier, and mannitol, which does not. Anaesthetized rats received a bolus injection into the left carotid artery of [14C]iodoantipyrine (0.25 μCi) combined with [3H]mannitol, [3H]devazepide or [3H]A-65186 (1 μCi each). Rats were decapitated 12 s after injection and the brains were removed. Four samples of left cerebrum (ca 100 mg each) were solubilized overnight and 14C and 3H activity were measured. The brain-uptake index for each test compound was determined as [(3H/14C for sample)]/[(3H/14C for injectate)] x 100, with a value of 100 representing blood-brain barrier permeability equal to that for iodoantipyrine. The brain-uptake index (mean ± s.e.m.) was 1.6 ± 0.3 for [3H]mannitol (n = 5), 90.6 ± 4.1 for [3H]devazepide (n = 7, P <0.001 compared with mannitol) and 3.5 ± 0.7 for [3H]A-65186 (n = 4, P > 0.05 compared with mannitol, P <0.001 compared with devazepide). Thus, devazepide readily penetrated the blood-brain barrier whereas A-65186 did not. It is concluded that devazepide and A-65186 are likely to be useful pharmacological tools for determining whether cholecystokinin is acting peripherally or at brain sites beyond the blood-brain barrier to produce satiety or any other function mediated by the type A cholecystokinin receptor.
| Original language | English |
|---|---|
| Pages (from-to) | 917-920 |
| Number of pages | 4 |
| Journal | Journal of Pharmacy and Pharmacology |
| Volume | 51 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1999 |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Pharmaceutical Science
Cite this
Relative blood-brain barrier permeabilities of the cholecystokinin receptor antagonists devazepide and A-65186 in rats. / Woltman, Todd A.; Hulce, Martin; Reidelberger, Roger D.
In: Journal of Pharmacy and Pharmacology, Vol. 51, No. 8, 08.1999, p. 917-920.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Relative blood-brain barrier permeabilities of the cholecystokinin receptor antagonists devazepide and A-65186 in rats
AU - Woltman, Todd A.
AU - Hulce, Martin
AU - Reidelberger, Roger D.
PY - 1999/8
Y1 - 1999/8
N2 - The blood-brain barrier permeabilities of the type-A cholecystokinin receptor antagonists devazepide and A-65186 (N(α)-3-quinolinoyl-D-Glu-N,N-dipentylamide) have been compared with those of the reference compounds iodoantipyrine, which readily penetrates the blood-brain barrier, and mannitol, which does not. Anaesthetized rats received a bolus injection into the left carotid artery of [14C]iodoantipyrine (0.25 μCi) combined with [3H]mannitol, [3H]devazepide or [3H]A-65186 (1 μCi each). Rats were decapitated 12 s after injection and the brains were removed. Four samples of left cerebrum (ca 100 mg each) were solubilized overnight and 14C and 3H activity were measured. The brain-uptake index for each test compound was determined as [(3H/14C for sample)]/[(3H/14C for injectate)] x 100, with a value of 100 representing blood-brain barrier permeability equal to that for iodoantipyrine. The brain-uptake index (mean ± s.e.m.) was 1.6 ± 0.3 for [3H]mannitol (n = 5), 90.6 ± 4.1 for [3H]devazepide (n = 7, P <0.001 compared with mannitol) and 3.5 ± 0.7 for [3H]A-65186 (n = 4, P > 0.05 compared with mannitol, P <0.001 compared with devazepide). Thus, devazepide readily penetrated the blood-brain barrier whereas A-65186 did not. It is concluded that devazepide and A-65186 are likely to be useful pharmacological tools for determining whether cholecystokinin is acting peripherally or at brain sites beyond the blood-brain barrier to produce satiety or any other function mediated by the type A cholecystokinin receptor.
AB - The blood-brain barrier permeabilities of the type-A cholecystokinin receptor antagonists devazepide and A-65186 (N(α)-3-quinolinoyl-D-Glu-N,N-dipentylamide) have been compared with those of the reference compounds iodoantipyrine, which readily penetrates the blood-brain barrier, and mannitol, which does not. Anaesthetized rats received a bolus injection into the left carotid artery of [14C]iodoantipyrine (0.25 μCi) combined with [3H]mannitol, [3H]devazepide or [3H]A-65186 (1 μCi each). Rats were decapitated 12 s after injection and the brains were removed. Four samples of left cerebrum (ca 100 mg each) were solubilized overnight and 14C and 3H activity were measured. The brain-uptake index for each test compound was determined as [(3H/14C for sample)]/[(3H/14C for injectate)] x 100, with a value of 100 representing blood-brain barrier permeability equal to that for iodoantipyrine. The brain-uptake index (mean ± s.e.m.) was 1.6 ± 0.3 for [3H]mannitol (n = 5), 90.6 ± 4.1 for [3H]devazepide (n = 7, P <0.001 compared with mannitol) and 3.5 ± 0.7 for [3H]A-65186 (n = 4, P > 0.05 compared with mannitol, P <0.001 compared with devazepide). Thus, devazepide readily penetrated the blood-brain barrier whereas A-65186 did not. It is concluded that devazepide and A-65186 are likely to be useful pharmacological tools for determining whether cholecystokinin is acting peripherally or at brain sites beyond the blood-brain barrier to produce satiety or any other function mediated by the type A cholecystokinin receptor.
UR - http://www.scopus.com/inward/record.url?scp=0032861788&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032861788&partnerID=8YFLogxK
U2 - 10.1211/0022357991773348
DO - 10.1211/0022357991773348
M3 - Article
C2 - 10504030
AN - SCOPUS:0032861788
VL - 51
SP - 917
EP - 920
JO - Journal of Pharmacy and Pharmacology
JF - Journal of Pharmacy and Pharmacology
SN - 0022-3573
IS - 8
ER -