Relative blood-brain barrier permeabilities of the cholecystokinin receptor antagonists devazepide and A-65186 in rats

Todd A. Woltman, Martin Hulce, Roger D. Reidelberger

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 languageEnglish
Pages (from-to)917-920
Number of pages4
JournalJournal of Pharmacy and Pharmacology
Volume51
Issue number8
DOIs
StatePublished - Aug 1999

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A 65186
Devazepide
Cholecystokinin Receptors
Blood-Brain Barrier
Permeability
Mannitol
Cholecystokinin A Receptor
Brain
Injections
Cholecystokinin
Cerebrum
Carotid Arteries
Pharmacology

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 journalArticle

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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.",
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