Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR.

Impaired activity of the chloride channel CFTR is the cause of cystic fibrosis. 14-3-3 proteins have been shown to stabilize CFTR and increase its biogenesis and activity. Here, we report the identification and mechanism of action of a macrocycle stabilizing the 14-3-3/CFTR complex.

Contribution of protein binding to the pharmacokinetics of the ghrelin receptor agonist TZP-101 in healthy volunteers and adults with symptomatic gastroparesis: two randomized, double-blind studies and a binding profile study.

Background And Objective: TZP-101 is a selective, small molecule ghrelin receptor agonist in clinical development for the treatment of gastric motility disorders. The objectives of this study was to assess pharmacokinetic parameters of TZP-101 after multiple- and single-dose administration to healthy subjects and patients with gastroparesis, respectively, and to determine the contribution of protein binding to its pharmacokinetic behaviour.

Methods: Pharmacokinetics following 30-minute intravenous infusions of single (160-600 microg/kg) doses of TZP-101 in patients with gastroparesis and multiple (80-600 mug/kg/day) doses of TZP-101 in healthy subjects were characterized.

Effect of TZP-201, a novel motilin receptor antagonist, in the colon of the musk shrew (Suncus murinus).

Objectives: Motilin is the main gut peptide that stimulates propulsive motility in the upper gastrointestinal (GI) tract. Motilin receptors exist in the colon but little is known about their functional role, and species-dependent differences present a major obstacle to understanding the physiological significance and potential therapeutic implications of motilin receptors in the colon. Our study aimed to define whether a motilin receptor is functionally expressed in the colon of the Asian musk (or house) shrew (Suncus murinus) and to investigate the effect of a novel motilin receptor antagonist, TZP-201.

Effect of the ghrelin receptor agonist TZP-101 on colonic transit in a rat model of postoperative ileus.

Ghrelin, the natural ligand of the growth hormone secretagogue receptor (ghrelin receptor), is an orexigenic gut hormone with prokinetic action in the upper gastrointestinal tract. Previously we have shown in a rodent model of postoperative ileus that the synthetic ghrelin receptor agonist TZP-101 prevents the delay in gastric emptying and improves small intestinal transit. The goal of the present study was to investigate whether TZP-101 affects colonic transit and food intake in rats with postoperative ileus.

Suppression of peroxisomal enzyme activities and cytochrome P450 4A isozyme expression by congeneric polybrominated and polychlorinated biphenyls.

The purpose of this study was to determine the effects of PCBs and PBBs on peroxisome proliferator-activated receptor-alpha-(PPARalpha-) associated enzyme activities or protein levels. Male Sprague-Dawley rats were administered a single IP injection (150 mu mol/kg) of either 3,3',4,4'-tetrabromobiphenyl, 3,3',4,4'-tetrachlorobiphenyl, 3,3',5,5'-tetrabromobiphenyl, 2',3,3',4,5-pentachlorobiphenyl, 3,3',4,4',5-pentachlorobiphenyl, 2,2',3,3',5,5'-hexachlorobiphenyl, or 3,3',4,4',5,5'-hexabromobiphenyl in corn oil (10 ml/kg). One week later, the activities of catalase, peroxisomal fatty acyl-CoA oxidase, and peroxisomal beta-oxidation as well as cytochrome P450 4A (CYP4A) protein content were determined in subcellular liver fractions.