Cholecystokinin receptor ligands

Gastrin and cholecystokinin receptor ligands consisting of lH-imidazole-4-yl-benzooxazole derivatives, (II), prepared by Kalindjian (3) were effective in controlling excess gastric acid secretion. 

Kalindjian, S.B. Black, J.W. Hull, Robert A. D. Shankley, N. P. Mesens, J. L. Andries L. J. Preparation and pharmaceutical compositions of gastrin/cholecystokinin receptor ligands with proton pump inhibitors. PCT Int. Appl. (2001), Patent No. WO 2001085167 Application WO 2001-GB1963 20010504. 

Newel experimental approaches to anxiety therapy include ligands interacting with the ligand-gated ion channels that are selectively activated by nicotine, C qH 4N2 (87), the well-known active ingredient of cigarettes which has anxiolytic actions (42). Cholecystokinin B receptor ligands, specifically the dipeptoid, CI-988 [130404-91 -0] 02 1142 40 (88) have demonstrated anxiolytic activity ia preclinical models (43). 

The BZ stmcture also has provided a molecular scaffold for a number of peptide receptor ligands (26). Antagonists for the cholecystokinin (CCK-A) receptor, eg, devazepide (65), the thyrotropin-releasing hormone (TRH) receptor, eg, midazolam (66), and the /i -opiate receptor, eg, tifluadom (67), as well as a series of ras famyl transferase inhibitors, eg, BZA-2B (68) (30) have been identified (Table 4). 

Substances with a neuromodulatory effect on brain neurotransmitters by direct actions of specific receptors that modify the actions of the transmitters listed include prostaglandins, adenosine, enkephalins, substance P, cholecystokinin, endorphins, endogenous benzodiazepine receptor ligands, and possibly histamine. CNS, central nervous system. NMDA, N-methyl-D-aspartate. Strych, strychnine. 

Phthalimidomethyl-substituted 477-pyrido[4,3-( ]-l-thia-2,4-diazine 1,1-dioxide derivative 125 undergoes hydrazino-lysis to produce the (7-3-aminomethyl-substituted product, which is then acylated to yield the amido adducts 126 (R = H, Ph R =Ar, NHAr) as potential cholecystokinin/gastric receptor ligands (Equation 17) <1997BSB781>. Similar acylation chemistry has been applied to the synthesis of related 5-(methylamides) of 2/7-benzo-l-thia-2,4-diazine 1,1-dioxides (see Section 9.05.9.1.3) <2001CHE237>. 

Heating substrates such as sulfonamide 182 without solvent also results in cyclization via condensation (—H2O) to provide 3-cyclopentyl-4i/-pyrido[4,3-f]-l-thia-2,4-diazine 1,1-dioxide 183 (Equation 34) <1996JME937>. Similarly, heating sulfonamides 184 (R = Me, At R = H, Br) neat gives access to potential cholecystokinin/gastrin receptor ligands such as 185 (Equation 35) <1998EJP29>. 

HGnn, J. Maigret, B. Tarek, M. Escrieut, C. Fourmy, D. Chipot, C., Probing a model of a GPCR/ligand complex in an explicit membrane environment. The human cholecystokinin-1 receptor, Biophys. J. 2006, 90, 1232-1240. 

Dorow R, Horowski R, Paschelke G, Amin M (1983) Severe anxiety induced by EG 7142, a beta-carboline ligand for benzodiazepine receptors. Lancet 2 98-99 Erankland PW, Josselyn SA, Bradwejn J, Vaccarino PJ, Yeomans JS (1997) Activation of amygdala cholecystokinin B receptors potentiates the acoustic startle response in the rat. J Neurosci 17 1838-1847... 

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. 

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