Cholecystokinin-B receptor antagonists

For the synthesis of cholecystokinin-B receptor antagonists by Lowe III and coworkers [70], the amino benzazepin-2-one (47) was resolved into single stereoisomers by the protocol shown in Scheme 5.21 (for clarity, only single stereoisomers depicted). The notable feature in this instance is the selective removal of the L-phenylalanine auxiliary by Edman degradation in the presence of additional amide linkages. 

In the synthesis of Cholecystokinin-B receptor antagonists, a benzodiazepin intermediate bearing an isocyanato group plays a key role. It is prepared from the corresponding amine 423 by carbonylation with phosgene in 98% yield [292]. 

Lowe IIIJA, Hageman DL, Drozda SE, McLean S, Bryce DK, Crawford RT, Zorn S, Morrone J, Bordner J. 5-Phenyl-3-ureidobenzazepin-2-ones as cholecystokinin-B receptor antagonists./. Afefi . Chem. 1994 37(22) 3789-3811. 

Bradwejn J, Koszycki D, Payeur R Study of the replication of action of cholecystokinin in panic disorders. Am J Psychiatry 149 962-964, 1992c Bradwejn J, Koszycki D, Couetoux-Dutertre AC, et al L-365,260, a CCK-B receptor antagonist, blocks CCK-4 panic (oral presentation). Presented at the annual meeting of the Anxiety Disorders Association of America (NR 235), Charleston, SC, March 20, 1993... 

Huganir RL, Greengard P Regulation of neurotransmitter receptor desensitization by protein phosphorylation. Neuron 5 555-567, 1990 Hughes J, Boden P, Costall B, et al Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci U S A 87 6728-6732, 1990... 

Path A leads to tryptophan derivatives (116), some of which are potent cholecystoki-nin antagonists (73). Some quinazolinone derivatives (117) of disconnection pathway B showed extremely high potency and excellent selectivity as cholecystokinin-B receptor sub-type ligands (44). A combination of X-ray crystallography and computational chemistry was used in the decision-making process in the bond disconnection (44) and in the design cf the specific target molecules. 

One of the important commercial routes to 1,4-benzodiazepines from 2-aminobenzophenones involves reaction of an AT-acylated analogue bearing a leaving group in the acyl chain with a source of ammonia <84CHEC-I(7)593>. One example of this reaction was used to synthesize an intermediate (140) for a cholecystokinin type B receptor antagonist (Equation (7)) <93BMC1919>. 

Beinhrom, M., Lee, Y.-M., McBride, E.W., Quinn, S.M. and Kopin, A.S. (1993) A single amino acid of the cholecystokinin-B 1 gastrin receptor determines specificity for non-peptide antagonists. Nature 362 348-351. 

Gilbert, J.D., Hand, E.L., Yuan, A.S., Olah, TV. and Covey T.R. (1992) Determination of L-365,260, a new cholecystokinin receptor (CCK-B) antagonist, in plasma by liquid chromatography/atmospheric pressure chemical ionisation mass sectrometry Biological Mass Spectrometry, 21 (2), 63-68. 

Lesch KP, Wiesmann M, Hoh A (1992) 5-HTlA receptor-effector system responsivity in panic disorder. Psychopharmacology (Berl) 106 111-117 Levin AP, Doran AR, Liebowitz MR, Fyer AJ, Klein DF, Paul SM (1987) Pituitary adrenocortical unresponsiveness in lactate-induced panic. Psychiatry Res 21 23-32 Lines C, Challenor J, Traub M (1995) Cholecystokinin and anxiety in normal volunteers—an investigation of the anxiogenic properties of pentagastrin and reversal by the cholecystokinin receptor subtype-b-antagonist L-365,260. Br J Clin Pharmacol 39 235-242 Low K, Crestani F, Keist R, Benke D, Brunig I (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290 131-134 Lucki I (1996) Serotonin receptor specificity in anxiety disorders. J Clin Psychiatry 57(Suppl 6) 5-10... 

Cholecystokinin (CCK) The tetrapeptide CCK causes more panic attacks when infused into patients with panic disorder than it does in normal volunteers, which suggests increased sensitivity of the brain type of CCK receptor, known as CCK-B. Unfortunately, in early investigations CCK-B antagonists did not appear to be effective for panic disorder. Nevertheless, agents with novel pharmacological mechanisms of action are sometimes evaluated for their potential antipanic actions by testing whether they can block CCK-induced panic attacks. 

Cholecystokinin. Cholecystokinin (CCK) is also colocalized with dopaminergic neurons and has two receptor subtypes, CCK-A being predominantly outside of and CCK-B within the central nervous system. Studies of CCK agonists and antagonists to date have not given clear clues as to their potential for therapeutic actions in schizophrenia. 

Lines C, Challenor J, Traub M. Cholecystokinin and anxiety in normal volunteers an investigation of the anxiogenic properties of pentagastrin and reversal by the cholecystokinin receptor subtype B antagonist L-365,260. Br J Clin Pharmacol 1995 39(3) 235-42. 

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