Name:	Linopirdine
Other Names:	DuP996
Development Status:	investigational in U.S.
FDA Phase:	Discontinued
Primary Medical Role:	Potential treatment for Alzheimer's disease.
Role in Alzheimer's Disease:	Improvement of cognitive symptoms.
Pharmacological Role:	Linopirdine enhances the stimulus-evoked but not basal release of several neurotransmitters including ACh, DA, 5- HT and Glu. It has been shown to enhance ACh release in the hippocampus in vivo. The mechanism whereby linopirdine enhances acetylcholine release has been proposed to involve inhibition of the M-type K+ current (IM).
Side Effects:	The compound has a low potential to produce side effects at pharmacodynamic active doses. The most frequently reported adverse event was headache.
Evidence pro its efficacy:	A putative cognition enhancing drug that increases acetylcholine release in rat brain tissue and improves performance in animal models of learning and memory.
Evidence con its efficacy:	Linopirdine does not improve memory performance either in explicit, implicit or primary tests in memory-imparied elderly subjects.
Notes:	Discontinued after inconclusive results in Phase III trials.

References

Borjesson A, Karlsson T, Adolfsson R, Ronnlund M, Nilsson L. Linopirdine (DUP 996): cholinergic treatment of older adults using successive and non-successive tests. Neuropsychobiology. 1999;40(2):78-85. Abstract

Earl RA, Zaczek R, Teleha CA, Fisher BN, Maciag CM, Marynowski ME, Logue AR, Tam SW, Tinker WJ, Huang SM, Chorvat RJ. 2-Fluoro-4-pyridinylmethyl analogues of linopirdine as orally active acetylcholine release- enhancing agents with good efficacy and duration of action. J Med Chem. 1998 Nov 5;41(23):4615-22. Abstract

Schnee ME, Brown BS. Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage- dependent and calcium-activated potassium currents in hippocampal neurons. J Pharmacol Exp Ther. 1998 Aug;286 (2):709-17. Abstract

Noda M, Obana M, Akaike N. Inhibition of M-type K+ current by linopirdine, a neurotransmitter-release enhancer, in NG108-15 neuronal cells and rat cerebral neurons in culture. Brain Res. 1998 Jun 1;794(2):274-80. Abstract

van Dyck CH, Lin CH, Robinson R, Cellar J, Smith EO, Nelson JC, Arnsten AF, Hoffer PB. The acetylcholine releaser linopirdine increases parietal regional cerebral blood flow in Alzheimer's disease. Psychopharmacology (Berl). 1997 Aug;132(3):217-26. Abstract

Rockwood K, Beattie BL, Eastwood MR, Feldman H, Mohr E, Pryse-Phillips W, Gauthier S. A randomized, controlled trial of linopirdine in the treatment of Alzheimer's disease. Can J Neurol Sci. 1997 May;24(2):140-5. Abstract

Lamas JA, Selyanko AA, Brown DA. Effects of a cognition- enhancer, linopirdine (DuP 996), on M-type potassium currents (IK(M)) and some other voltage- and ligand-gated membrane currents in rat sympathetic neurons. Eur J Neurosci. 1997 Mar;9(3):605-16. Abstract

Tam SW, Zaczek R. Linopirdine. A depolarization-activated releaser of transmitters for treatment of dementia. Adv Exp Med Biol. 1995;363:47-56. Abstract