David A. Kendrick

Structure-activity relationships of phenothiazines in inhibiting lymphocyte motility as determined by a novel flow cytometric assay

Lymphocyte motility is highly dependent on rapid changes in cell shape. The human T-lymphoma cell line, MOLT-4, is constitutively shape-changing and motile, and both of these properties can be inhibited by the phenothiazine, chlorpromazine, as assessed by video analysis and migration across polycarbonate filters. In this paper, the light-scattering facility of a flow cytometer has been used to establish a simpler and more quantitative means of measuring changes in shape. By this method, the structure activity relationship (SAR) of phenothiazines and related compounds has been determined. The most active compounds had the tricyclic phenothiazine nucleus with a constrained dialkylaminoalkyl substituent at the nitrogen. The SAR for inhibition of lymphocyte motility differs from those reported for neuroleptic effects and for inhibition of PKC or calmodulin. Phenothiazine concentrations that inhibited lymphocyte shape-changing resulted in reduced F-actin concentrations. This indicates that the probable mode of action is disruption of mechanisms regulating actin polymerisation.

Synthesis and biological activity of 1-alkylcarbonylmethyl analogues of YM022

Abstract A novel series of 1-alkylcarbonylmethyl analogues of the potent gastrin/CCK-B receptor antagonist YM022 have been prepared. A number of analogues retained good affinity for the gastrin/CCK-B receptor and one compound (6d) showed improved binding and enhanced selectivity for this receptor over CCK-A. A second compound (6j) gave improved in vivo inhibition of gastric acid secretion in rats. Both analogues were shown to have significantly better activity in the same model following i.d. dosing than either YM022 or L-365,260.

Synthesis and biological activity of 5-heteroaryl benzodiazepines: analogues of YM022

Abstract A novel series of analogues of the potent gastrin/CCK-B receptor antagonist YM022 have been prepared which incorporate 5- and 6-membered heteroaromatic rings in the benzodiazepine 5-position. The 5-(2-pyridyl) derivatives in particular retained good in vitro and in vivo potency and one such compound 9i was shown to inhibit acid secretion after oral dosing in dogs. Improved bioavailability for 9i over the 5-phenyl analogue, 9h was demonstrated in rats.

Cholecystokinin analogues: The ergopeptine alkaloids as models of the active conformation of CCK

Abstract Ergotamine was shown to inhibit the binding of radiolabelled CCK to both CCK-A and CCK-B receptors with a relatively modest potency (IC50 = 30 μM and 17 μM respectively).

Identification and biological activity of novel peptidomimetic gastrin/CCK-B receptor agonists

Abstract The design, synthesis and biological activity of two novel series of compounds derived from the basic Boc-CCK-4 structure which provide potent ligands for the gastrin/CCK-B receptor is outlined. Within these series, new pseudopeptide compounds were discovered which unexpectedly were functional agonists in vivo, as shown by their ability to stimulate basal gastric acid secretion in rats, an effect which was blocked by the potent gastrin/CCK-B receptor antagonist YM022.