VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux.

Abstract

Recent evidence suggests that 5-hydroxytryptamine (5-HT)(4) receptor activity enhances cognition and provides neuroprotection. Here we report the effects of VRX-03011, a novel partial 5-HT(4) agonist, that is both potent (K(i) approximately 30 nM) and highly selective (K(i) > 5 microM for all other 5-HT receptors tested). In separate experiments, rats received VRX-03011 (0.1-10 mg/kg i.p.) 30 min prior to spontaneous alternation testing in a no-delay or a 30-s delay condition. VRX-03011 (1, 5 and 10 mg/kg, but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation performance while none of the doses enhanced performance in the no-delay test. VRX-03011 (1 and 5 mg/kg) concomitantly enhanced hippocampal acetylcholine output and delayed spontaneous alternation scores compared to that of vehicle controls, but had no effect on hippocampal acetylcholine release under a resting condition. Moreover, suboptimal doses of VRX-03011 and the acetylcholinesterase inhibitor galanthamine combined to enhance memory. VRX-03011 also regulated amyloid precursor protein (APP) metabolism by inducing a concentration-dependent increase in the non-amyloidogenic soluble form of APP (sAPPalpha) with an EC(50) approximately 1--10 nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC(50) > 10 microM and did not alter rat intestinal transit at doses up to 10 mg/kg. These findings suggest that VRX-03011 may represent a novel treatment for Alzheimer's disease that reduces cognitive impairments and provides neuroprotection without gastrointestinal side effects.

• Authors: Eric G Mohler, Sharon Shacham, Silvia Noiman, Frank Lezoualc'h, Sylvain Robert, Monique Gastineau, Joseph Rutkowski, Yael Marantz, Aline Dumuis, Joel Bockaert, Paul E Gold, Michael E Ragozzino
• Journal: Neuropharmacology (Neuropharmacology) Vol. 53 Issue 4 Pg. 563-73 (Sep 2007) ISSN: 0028-3908 [Print] England
• PMID: 17692343 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)thieno(2,3-b)pyridine-5-carboxamide
• Ligands
• Pyridones
• Serotonin Receptor Agonists
• Thiophenes
• Receptors, Serotonin, 5-HT4
• Acetylcholine

Topics

• Acetylcholine (physiology)
• Animals
• Cognition (drug effects, physiology)
• Hippocampus (cytology, drug effects, physiology)
• Ligands
• Memory (drug effects, physiology)
• Models, Animal
• Pyridones (pharmacology)
• Rats
• Receptors, Serotonin, 5-HT4 (drug effects, genetics, physiology)
• Serotonin Receptor Agonists (pharmacology)
• Thiophenes (pharmacology)
• Transfection