TC-2559: a novel orally active ligand selective at neuronal acetylcholine receptors.
TC-2559 [(E)-N-Methyl-4-[3-(5-ethoxypyridin)yl]-3-buten-1-amine] is a novel nicotinic agonist markedly more selective than recently reported novel nicotinic receptor ligands (selectivity ratio for central nervous system (CNS) to peripheral nervous system (PNS)>4000). TC-2559 competes effectively with [3H]-nicotine binding (K(i)=5 nM) but not with [125I]-bungarotoxin (>50,000 nM). Dopamine release from striatal synaptosomes and ion flux from thalamic synaptosomes indicate that TC-2559 is potent and efficacious in the activation of CNS receptors and significantly reduced glutamate-induced neurotoxicity in vitro. TC-2559 has no detectable effects on muscle and ganglion-type nicotinic acetylcholine receptors at concentrations up to 1 mM. TC-2559 significantly attenuates scopolamine-induced cognitive deficits in a step-through passive avoidance task. Acute and repeated oral dosing of TC-2559 enhances performance in a radial arm maze task. In contrast to the effects of equimolar concentrations of (-) nicotine, TC-2559 does not induce hypothermia and locomotor activity is not enhanced following repeated daily administration of 14 days. TC-2559 has a markedly enhanced CNS-PNS selectivity ratio and an intra-CNS selectivity as evidenced by the improved cognition without increased locomotor activity. The in vitro and in vivo studies in the present study suggest that TC-2559 has the desired profile to be further evaluated as a potential therapeutic agent for neurodegenerative diseases.
Bencherif
M
M
Targacept, Inc., Research and Development, BGTC Bldg. 611-1/ 212D, Winston-Salem, NC 27102, USA. Benchem@Targacept.com
Bane
A J
AJ
Miller
C H
CH
Dull
G M
GM
Gatto
G J
GJ
D000647:Amnesia / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D008024:Ligands; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000187:drug effects*; D012414:Rubidium Radioisotopes; D012601:Scopolamine; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D008024:Ligands; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D011725:Pyridines; D011950:Receptors, Cholinergic; D012414:Rubidium Radioisotopes; C419442:TC 2559; D012601:Scopolamine; D004298:Dopamine