F15599, a preferential post-synaptic 5-HT1A receptor agonist: activity in models of cognition in comparison with reference 5-HT1A receptor agonists.

Abstract

We assessed the activity of F15599, a selective and high efficacy 5-HT(1A) agonist that preferentially activates post- versus pre-synaptic receptors, in rat cognition/memory models. F15599 (0.16 mg/kg i.p.) partially alleviated detrimental effects of phencyclidine on working and reference memory deficit in a hole-board model. It also attenuated phencyclidine-induced deficit of cognitive flexibility in a reversal learning task, without effects of its own. F13714 (0.04 mg/kg) a chemical congener of F15599, and 8-OH-DPAT (0.01 or 0.16), were inactive against these phencyclidine-induced deficits, and/or even worsened basal performances. F15599 (0.04-2.5) was less disruptive than F13714 (0.005-0.16) or 8-OH-DPAT (0.01-0.63), on basal performance in models of attention (5-choice serial reaction time task) and working memory (delayed non-matching to position). Finally, unlike either comparator, F15599 reduced PPI with modest potency and only partially. To conclude, F15599, in models of memory/cognition, has a more favourable profile than F13714 and 8-OH-DPAT. This suggests that preferential activation of post-synaptic 5-HT(1A) receptors could prove useful in pathologies characterized by cognitive/memory deficiencies, such as schizophrenia and depression.

• Authors: Ronan Depoortère, Agnès L Auclair, Laurent Bardin, Francis C Colpaert, Bernard Vacher, Adrian Newman-Tancredi
• Journal: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology (Eur Neuropsychopharmacol) Vol. 20 Issue 9 Pg. 641-54 (Sep 2010) ISSN: 1873-7862 [Electronic] Netherlands
• PMID: 20488670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier B.V. All rights reserved.

Chemical References

• 3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methyl-6-methylaminopyridin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
• 3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
• Aminopyridines
• Enzyme Inhibitors
• Piperidines
• Pyrimidines
• Serotonin 5-HT1 Receptor Agonists
• Receptor, Serotonin, 5-HT1A
• 8-Hydroxy-2-(di-n-propylamino)tetralin
• Phencyclidine

Topics

• 8-Hydroxy-2-(di-n-propylamino)tetralin (metabolism, pharmacology)
• Aminopyridines (metabolism, pharmacology)
• Animals
• Cognition (drug effects)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Male
• Memory, Short-Term (drug effects)
• Phencyclidine (pharmacology)
• Piperidines (metabolism, pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (metabolism)
• Reflex, Startle (drug effects)
• Serotonin 5-HT1 Receptor Agonists (pharmacology)
• Signal Transduction