In the present study we have described an ex vivo binding assay in mice to measure the central nervous system (CNS) activity of systemically administered CCKB receptor antagonists. This assay incorporated a transcardiac perfusion step to remove the residual blood from the brain, which otherwise may result in an overestimation of CNS activity. The benzodiazepine CCKB receptor antagonist L-365,260 had marked CNS activity in this assay following i.v. (ED50 12.0 mg/kg) and p.o. (ED50 20.0 mg/kg) administration, whereas the dipeptoid CCKB receptor antagonist, CI988 exhibited relatively weak CNS activity following i.v. injection (ED50 > 30.0 mg/kg). In contrast, following i.c.v. administration, CI988 potently inhibited ex vivo binding of [125I]Bolton Hunter-CCK-8S to mouse brain. The recently described acidic tetrazole CCKB receptor antagonist, L-368,935 had potent CNS activity with an ED50 of 5.6 mg/kg i.v. and an ED50 of 1.9 micrograms/kg i.c.v. These studies suggest that the weak CNS activity of CI988 following systemic injection may, in part, be due to poor brain penetration and that the ex vivo binding assay is a useful way of assessing the brain penetration of CCKB receptor antagonists.

01 Mar 1994·Annals of the New York Academy of SciencesQ2 · CROSS-FIELD

A Second Generation of Non‐Peptide Cholecystokinin Receptor Antagonists and Their Possible Therapeutic Potential

Q2 · CROSS-FIELD

Review

Author: M. G. Bock ; G. R. Marshall ; K. Chapman ; E. C. Mellin ; R. M. DiPARDO ; A. Fletcher ; S. Patel ; R. J. Hargreaves ; K. Scholey ; S. B. Freedman ; J. A. Kemp ; A. J. Smith ; R. M. Freidinger

The profile of an acidic series of benzodiazepine CCK-B receptor antagonists is described. The tetrazolyl urea derivative L-368,935 had high affinity (CCK-B IC50 0.1 nM) and was one of the most selective (CCK-B/CCK-A 10,000) CCK-B antagonists known. L-368,935 was a CCK-B antagonist with high affinity on the rat ventromedial hypothalamic slice preparation (Kb 0.6 nM) and also blocked pentagastrin-induced calcium mobilization in GH3 cells. L-368,935 had potent in vivo activity and antagonized pentagastrin-induced gastric acid secretion in the anesthetized rat and CCK-8S-induced aspartate release using microdialysis in the striatum of conscious rats. Activity within the central nervous system was confirmed by a mouse ex vivo binding assay and by direct measurement of the compound within the central nervous system using an HPLC assay. A second generation of CCK-B receptor antagonists such as L-368,935 will be important in determining the therapeutic potential of this class of compound in man.

01 Mar 1994·Journal of Medicinal ChemistryQ1 · MEDICINE

Second-Generation Benzodiazepine CCK-B Antagonists. Development of Subnanomolar Analogs with Selectivity and Water Solubility

Q1 · MEDICINE

Review

Author: Bock, Mark G. ; Newton, Randall C. ; Mellin, Eva C. ; Smith, Alison J. ; DiPardo, Robert M. ; Kemp, John A. ; Veber, Daniel F. ; Freedman, Stephen B. ; Patel, Smita

Potent 3-arylureido-5-phenyl-1,4-benzodiazepines that are highly selective antagonists for the cholecystokinin-B (CCK-B) receptor are described.The two leading compounds derived from this investigation, L-368,935 and L-369,466, are water soluble, show high affinity for the CCK-B receptor from human cerebral cortex, are functional antagonists in vitro, and show no agonist activity.The brain penetrability of these compounds is relatively low, as determined by an ex vivo binding assay in the mouse.The oral bioavailability of these compounds, coupled with their favorable physicochem. and pharmacokinetic properties makes these analogs ideal candidates for the study of peripherally mediated physiol. effects attributed to CCK-B receptors.

100 Deals associated with L-368935

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Discovery	US	Merck & Co., Inc.	-
Pain	Discovery	US	Merck & Co., Inc.	-
Schizophrenia	Discovery	US	Merck & Co., Inc.	-

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