Ezetimibe potently inhibits cholesterol absorption but does not affect acute hepatic or intestinal cholesterol synthesis in rats

1. Ezetimibe (1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone) and its analog SCH48461 are potent and selective cholesterol absorption inhibitors that inhibit the transport of cholesterol across the intestinal wall, thereby lowering plasma cholesterol. 2. After a dose response for ezetimibe in rats was established, experiments were conducted to determine whether acute administration could alter hepatic or intestinal cholesterol synthesis. To determine whether this class of intestinal cholesterol absorption inhibitors could discriminate between newly synthesized cholesterol in the intestine versus exogenously administered cholesterol, rats were intraduodenally dosed with (14)C-cholesterol and (3)H-mevalonate, and mesenteric lymph was analyzed for radiolabeled cholesterol and cholesteryl ester content. 3. Ezetimibe attenuated diet-induced hypercholesterolemia 60–94% at doses of 0.1–3 mg kg(−1) in rats. A single administration of ezetimibe did not have a direct effect on intestinal or hepatic cholesterol synthesis, while ketoconazole significantly inhibited cholesterol synthesis after a single dose. The ezetimibe analog, SCH48461, inhibited the movement of exogenously administered cholesterol into lymph, but did not affect the appearance of newly synthesized cholesterol into lymph. 4. These data suggest that this class of cholesterol absorption inhibitors does discriminate by blocking the movement of exogenous cholesterol in the enterocyte before it reaches the intracellular cholesterol pool to be incorporated into intestinal lipoproteins, without affecting the incorporation of newly synthesized cholesterol into intestinal lipoproteins

Nociceptin inhibits cough in the guinea-pig by activation of ORL(1) receptors

We studied the central and peripheral antitussive effect of ORL(1) receptor activation with nociceptin/orphanin FQ in conscious guinea-pigs. In guinea-pig cough studies, nociceptin/orphanin FQ (10, 30, and 90 μg) given directly into the CNS by an intracerebroventricular (i.c.v.) route inhibited cough elicited by capsaicin exposure by approximately 23, 29 and 52%, respectively. The antitussive activity of nociceptin/orphanin FQ (90 μg, i.c.v.) was blocked by the selective ORL(1) antagonist [Phe(1)γ(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) (180 μg, i.c.v.) and J113397 (10 mg kg(−1), i.p.) but not by the opioid antagonist, naltrexone (3 mg kg(−1), i.p.). Furthermore, intravenous (i.v.) nociceptin/orphanin FQ (1.0 and 3.0 mg kg(−1)) also inhibited cough approximately by 25 and 42%, respectively. These findings indicate that selective ORL(1) agonists display the potential to inhibit cough by both a central and peripheral mechanism, and potentially represent a novel therapeutic approach for the treatment of cough

The anxiolytic-like effects of the novel, orally active nociceptin NOP receptor agonist, 8-[bis(2-methylphenyl)methyl]-3-phenyl-8- azabicyclo[3.2.1]octan-3-ol (SCH 221510) JPET #136937 2 Running Title: Anxiolytic-like effects of the NOP agonist, SCH 22151

Abstract Orphanin FQ/nociceptin (OFQ/N) is the endogenously occurring peptide ligand for the nociceptin opioid receptor (NOP) that produces anxiolytic-like effects in mice and rats