The selective nicotinic acetylcholine receptor alpha7 agonist JN403 is active in animal models of cognition, sensory gating, epilepsy and pain.
Several lines of evidence suggest that the nicotinic acetylcholine receptor alpha7 (nAChR alpha7) is involved in central nervous system disorders like schizophrenia and Alzheimer's disease as well as in inflammatory disorders like sepsis and pancreatitis. The present article describes the in vivo effects of JN403, a compound recently characterized to be a potent and selective partial nAChR alpha7 agonist. JN403 rapidly penetrates into the brain after i.v. and after p.o. administration in mice and rats. In the social recognition test in mice JN403 facilitates learning/memory performance over a broad dose range. JN403 shows anxiolytic-like properties in the social exploration model in rats and the effects are retained after a 6h pre-treatment period and after subchronic administration. The effect on sensory inhibition was investigated in DBA/2 mice, a strain with reduced sensory inhibition under standard experimental conditions. Systemic administration of JN403 restores sensory gating in DBA/2 mice, both in anaesthetized and awake animals. Furthermore, JN403 shows anticonvulsant potential in the audiogenic seizure paradigm in DBA/2 mice. In the two models of permanent pain tested, JN403 produces a significant reversal of mechanical hyperalgesia. The onset was fast and the duration lasted for about 6h. Altogether, the present set of data suggests that nAChR alpha7 agonists, like JN403 may be beneficial for improving learning/memory performance, restoring sensory gating deficits, and alleviating pain, epileptic seizures and conditions of anxiety.
Feuerbach
Dominik
D
Novartis Institutes for BioMedical Research, WSJ386.725, 4002 Basel, Switzerland. dominik.feuerbach@novartis.com
Lingenhoehl
Kurt
K
Olpe
Hans-Rudolf
HR
Vassout
Annick
A
Gentsch
Conrad
C
Chaperon
Frederique
F
Nozulak
Joachim
J
Enz
Albert
A
Bilbe
Graeme
G
McAllister
Kevin
K
Hoyer
Daniel
D
D000161:Acoustic Stimulation / Q000009:adverse effects / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D002219:Carbamates / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D017288:Pain Threshold / Q000187:drug effects; D011812:Quinuclidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology; D055139:Sensory Gating / Q000187:drug effects*; D012919:Social Behavior; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor
C520400:(S)-(1-azabicyclo(2.2.2)oct-3-yl)carbamic acid (S)-1-(2-fluorophenyl) ethyl ester; D002219:Carbamates; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine