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P1‐309: Suvn‐d4010: A novel 5‐ht 4 receptor partial agonist for the treatment of Alzheimer's disease
Author(s) -
MuddageswaraRao,
Subramanian Ramkumar,
Medapati Rajesh Babu,
Abraham Renny,
Benade Vijay S.,
Raghava Veera,
Palacharla Chowdary,
Manoharan Arun Kumar,
Goyal Vinod Kumar,
Pandey Santosh Kumar,
Rasheed Mohammed Abdul,
Ravella Srinivasa Rao,
Nirogi Ramakrishna
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.524
Subject(s) - cholinergic , agonist , acetylcholine , partial agonist , neuroscience , pharmacology , receptor antagonist , cholinergic neuron , neuroprotection , psychology , medicine , chemistry , receptor , antagonist
Background: Serotonin receptor, subtype 4 (5-HT4) is involved in memory formation. It modulates the cholinergic pathway through the release of acetylcholine from the cholinergic neurons. Activation of 5-HT4 receptor directs processing of amyloid precursor protein (APP) towards non-amyloidogenic form and also promotes the formation of the neurotrophic sAPPa. Therefore 5-HT4 agonist may offer a unique treatment for Alzheimer’s disease (AD). Methods: The procognitive property of SUVN-D4010, a potent, selective and orally bioavailable 5-HT4 partial agonist was characterized in animals models of cognition like object recognition task, radial arm maze task and fear conditioning assay. The effect on the cholinergic neurotransmission was studied using brain microdialysis technique. In vivo receptor binding profile was measured using non-radiolabeled tracer in rats. The effect of SUVN-D4010 on the toxic b-amyloid and the neuroprotective sAPPa were evaluated in the preclinical species using ELISA kits. Safety, general toxicity and mutagenic potential of SUVND4010 were evaluated in rodents/non rodents and in vitro models. Results: SUVN-D4010 improved the episodic memory deficits in object recognition task. It also reversed the working and emotional memory deficits induced by scopolamine in radial arm maze task and fear conditioning assay. Oral administration of SUVN-D4010 significantly increased the brain acetylcholine levels. The effect on the cognition and cholinergic neurotransmission were blocked byGR 125478, a selective 5-HT4 antagonist. SUVN-D4010 showed significant 5-HT4 receptor occupancy at pharmacologically effective doses. A significant increase in cortical sAPPa and decrease in amyloid-b protein levels was also seen. SUVN-D4010 was well tolerated in animal toxicity studies and did not show any mutagenic potential. Conclusions: SUVN-D4010 is a novel, potent, selective, orally bioavailable, efficacious and a safe 5-HT4 receptor partial agonist. IND enabling GLP safety studies have been completed. US IND filing and Phase I studies are currently being planned.