Jann A. Nielsen

Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes

9-Amino-1,2,3,4-tetrahydroacridine (THA) has been reported to cause improvement in patients with senile dementia of the Alzheimers type. We have examined some effects of THA in vitro and in vivo to define its mechanism of action. In vitro, THA inhibits acetylcholinesterase (AChE) (IC50 = 223 nM) and blocks [3H]AFDX-116 (M2) and [3H]telenzepine (M1) binding (IC50 s of 1.5 and 9.1 microM respectively). In vivo levels of THA were 10-fold higher in brain than plasma following 3.2 mg/kg i.p., a dose which was found to be active in reversing amnesia induced by scopolamine assessed in T-maze tests in rats and passive avoidance tests in mice. Additionally, these brain concentrations were above the IC50 of THA for AChE inhibition. THA (5.6-17.8 mg/kg i.p.) also elevated acetylcholine levels in the rat CNS. THA-induced side effects were blocked by the central muscarinic antagonist, scopolamine, but not by the peripheral antagonists methscopolamine and glycopyrrolate, nor by nicotinic antagonists. We conclude that brain AChE inhibition by THA is sufficient to explain its purported therapeutic activity in Alzheimers disease and that its favorable brain/plasma distribution in vivo may account for its central cholinergic action without inducing the severe peripheral cholinergic effects typically seen with other AChE inhibitors.

Sertraline, a serotonin-uptake inhibitor, reduces food intake and body weight in lean rats and genetically obese mice.

Sertraline was found to inhibit weight gain and decrease food intake without affecting locomotion in rats and genetically obese (ob/ob) mice. Doses of 10, 17.8, and 32 mg/kg, administered intraperitoneally, (bid) significantly reduced the time rats spent in contact with their feeders and body weight in a dose-related manner. During a 5-d bid treatment regimen, vehicle-treated rats gained 37 +/- 3 g (mean +/- SEM), whereas animals treated with 32 mg sertraline/kg lost 34 +/- 4 g. The effects of sertraline on feeding and body weight in rats appeared to be specific because locomotor activity was not altered. In ob/ob mice, sertraline (44 mg/kg, ip, bid) lowered body weight relative to vehicle-treated controls for the duration of a 12-d study. There was no evidence for tolerance to the hypophagic and weight-loss effects of sertraline during either of the chronic dosing studies. These results suggest a potential role for sertraline in the treatment of human obesity.

CP-93,129: A Potent and Selective Agonist for the Serotonin (5-HT1B) Receptor and Rotationally Restricted Analog of RU-24,969

The in vitro and in vivo characteristics of CP-93,129 [Structure 1 in Figure 1, 3-(1,2,5,6-tetrahydropyrid-4-yl)-pyrrolo[3,2-b]pyrid-5-one] are described. This rotationally restricted phenolic analog of RU-24,969 is a potent (15 nm) and selective (200 × vs. the 5-HT1A receptor, 150 × vs. the 5-HT1D receptor) functional agonist for the 5-HT1B receptor. Direct infusion of CP-93, I29 into the paraventricular nucleus of the hypothalamus of rats significantly inhibits food intake, implicating the role of 5-HT1B receptors in regularing feeding behavior in rodents. CP-93,129 has also been shown to be biochemically discriminatory in its ability to selectively inhibit forskolin-stimulated adenylate cyclase activity only at the 5-HT1B receptor. The source of the selectivity of CP-93,129 appears to lie in the ability of a pyrrolo[3,2-b]pyrid5-one to act as a rotationally restricted bioisosteric replacement for 5-hydroxyindole.