- Email: [email protected]
Suvn-g3031, an h3 receptor inverse agonist, produces procognitive effects without affecting sleep in preclinical models
Poster Presentations: P1
significantly enhanced cognition in normal rat novel object recognition test. In rat hippocampus slice, this agent (300 nmol/L) significantly enhanced long term potentiation. This agent did not show anxiogenic-like or proconvulsant effects. Conclusions: We identified a novel GABAAa5 NAM which enhances cognition without anxiogenic or proconvulsant side effects.
P1-309
SUVN-D4010: A NOVEL 5-HT4 RECEPTOR PARTIAL AGONIST FOR THE TREATMENT OF ALZHEIMER’S DISEASE
NageswaraRao Muddana, Ramkumar Subramanian, Rajesh Babu Medapati, Renny Abraham, Vijay S. Benade, Veera Raghava, Chowdary Palacharla, Arun Kumar Manoharan, Vinod Kumar Goyal, Santosh Kumar Pandey, Mohammed Abdul Rasheed, Srinivasa Rao Ravella, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] 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 by GR 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.
P1-310
SUVN-G3031, AN H3 RECEPTOR INVERSE AGONIST, PRODUCES PROCOGNITIVE EFFECTS WITHOUT AFFECTING SLEEP IN PRECLINICAL MODELS
Vijay S. Benade, Saivishal Daripelli, Jagadeesh Babu Thentu, Arunkumar Manoharan, Rajesh Babu Medapati, Ramkumar Subramanian, Venkat Reddy Mekala, Anil K. Shinde, Rajesh Kumar Badange, Vinod Kumar Goyal, Santosh Kumar Pandey, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected]
P475
Background: Histamine H3 receptors play a critical role as a neuromodulator through its widespread distribution in the central nervous system. Blockade of this receptor augments the pre-synaptic release of histamine and other neurotransmitters including acetylcholine. Currently, several H3 receptor antagonists/inverse agonists are in different stages of clinical trials for the potential treatment of narcolepsy, cognitive impairments associated with Alzheimer’s disease, Parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder. Methods: In vivo receptor occupancy in rats was evaluated for SUVN-G3031 using non-radiolabled tracer. SUVN-G3031 was evaluated in H3 agonist induced dipsogenia assay, and rat models of cognition like object recognition task, T-maze and Morris water maze task. Effect of SUVN-G3031 on histamine and acetylcholine modulation in brain was studied using microdialysis. Electroencephalography was used to study the effects of SUVN-G3031 on wake promoting activity in rats. Safety of SUVN-G3031 was evaluated in rodents/ non rodents and In vitro models. Results: SUVNG3031 is one of the lead molecule with hKi of 8.7 nM and has more than 100 fold selectivity against the related GPCRs. SUVNG3031 exhibited desired pharmacokinetic property and brain penetration. This molecule exhibited an excellent separation between H3 affinity and hERG ion channel inhibition. SUVN-G3031 blocked R-a-methylhistamine induced water intake and increased telemethylhistamine levels in brain and cerebrospinal fluid. SUVNG3031 significantly reversed time induced memory deficit in object recognition test & T-maze task. It also reversed scopolamine induced memory deficit in Morris water maze task. Oral administration resulted in H3 receptor occupancy up to 85% in rats and significantly raised acetylcholine and histamine levels in the cortex. At therapeutically effective doses, SUVN-G3031 produced no change in the sleep/ wake profile of rats. SUVN-G3031 was well tolerated in toxicity studies in animals with wide margin of safety, and was found to be non genotoxic in bacterial reverse mutation assay and chromosomal aberration test in human lymphocytes. Conclusions: SUVN-G3031 produced procognitive effects in rats without affecting the sleep and it possess safety and desired pharmacokinetic profile for further development. First in human, US IND Phase-I studies are in progress to evaluate the safety, tolerability and pharmacokinetics of SUVN-G3031 in healthy adult human volunteers.
P1-311
THE 5-HT6 ANTAGONIST SUVN-502 POTENTIATES THE EFFECTS OF ACETYLCHOLINESTERASE INHIBITORS ON EXTRACELLULAR ACETYLCHOLINE LEVELS AND IN ANIMAL MODELS OF COGNITION
Gopinadh Bhyrapuneni, Vijay S. Benade, Venkatesh Kamuju, Ranjith Kumar Ponnamaneni, Shantaveer M. Irappanavar, Pradeep Jayarajan, Renny Abraham, Laxman Kota, Sangram Keshari Saraf, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: SUVN-502 is a potent and selective 5-HT6 antagonist being developed for the symptomatic treatment of Alzheimer’s disease. SUVN-502 is orally bioavailable and has adequate brain penetration. SUVN-502 exhibited pro-cognitive properties when tested in various rodent models. In rat brain microdialysis, SUVN-502 increased acetylcholine levels in brain regions involved in learning and memory, providing the neurochemical basis for the pro-cognitive effects in rodent models. Methods: SUVN-502 alone and in combination with acetylcholinesterase inhibitors (donepezil or rivastigmine) was evaluated in object recognition task. Effect of
significantly enhanced cognition in normal rat novel object recognition test. In rat hippocampus slice, this agent (300 nmol/L) significantly enhanced long term potentiation. This agent did not show anxiogenic-like or proconvulsant effects. Conclusions: We identified a novel GABAAa5 NAM which enhances cognition without anxiogenic or proconvulsant side effects.
P1-309
SUVN-D4010: A NOVEL 5-HT4 RECEPTOR PARTIAL AGONIST FOR THE TREATMENT OF ALZHEIMER’S DISEASE
NageswaraRao Muddana, Ramkumar Subramanian, Rajesh Babu Medapati, Renny Abraham, Vijay S. Benade, Veera Raghava, Chowdary Palacharla, Arun Kumar Manoharan, Vinod Kumar Goyal, Santosh Kumar Pandey, Mohammed Abdul Rasheed, Srinivasa Rao Ravella, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] 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 by GR 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.
P1-310
SUVN-G3031, AN H3 RECEPTOR INVERSE AGONIST, PRODUCES PROCOGNITIVE EFFECTS WITHOUT AFFECTING SLEEP IN PRECLINICAL MODELS
Vijay S. Benade, Saivishal Daripelli, Jagadeesh Babu Thentu, Arunkumar Manoharan, Rajesh Babu Medapati, Ramkumar Subramanian, Venkat Reddy Mekala, Anil K. Shinde, Rajesh Kumar Badange, Vinod Kumar Goyal, Santosh Kumar Pandey, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected]
P475
Background: Histamine H3 receptors play a critical role as a neuromodulator through its widespread distribution in the central nervous system. Blockade of this receptor augments the pre-synaptic release of histamine and other neurotransmitters including acetylcholine. Currently, several H3 receptor antagonists/inverse agonists are in different stages of clinical trials for the potential treatment of narcolepsy, cognitive impairments associated with Alzheimer’s disease, Parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder. Methods: In vivo receptor occupancy in rats was evaluated for SUVN-G3031 using non-radiolabled tracer. SUVN-G3031 was evaluated in H3 agonist induced dipsogenia assay, and rat models of cognition like object recognition task, T-maze and Morris water maze task. Effect of SUVN-G3031 on histamine and acetylcholine modulation in brain was studied using microdialysis. Electroencephalography was used to study the effects of SUVN-G3031 on wake promoting activity in rats. Safety of SUVN-G3031 was evaluated in rodents/ non rodents and In vitro models. Results: SUVNG3031 is one of the lead molecule with hKi of 8.7 nM and has more than 100 fold selectivity against the related GPCRs. SUVNG3031 exhibited desired pharmacokinetic property and brain penetration. This molecule exhibited an excellent separation between H3 affinity and hERG ion channel inhibition. SUVN-G3031 blocked R-a-methylhistamine induced water intake and increased telemethylhistamine levels in brain and cerebrospinal fluid. SUVNG3031 significantly reversed time induced memory deficit in object recognition test & T-maze task. It also reversed scopolamine induced memory deficit in Morris water maze task. Oral administration resulted in H3 receptor occupancy up to 85% in rats and significantly raised acetylcholine and histamine levels in the cortex. At therapeutically effective doses, SUVN-G3031 produced no change in the sleep/ wake profile of rats. SUVN-G3031 was well tolerated in toxicity studies in animals with wide margin of safety, and was found to be non genotoxic in bacterial reverse mutation assay and chromosomal aberration test in human lymphocytes. Conclusions: SUVN-G3031 produced procognitive effects in rats without affecting the sleep and it possess safety and desired pharmacokinetic profile for further development. First in human, US IND Phase-I studies are in progress to evaluate the safety, tolerability and pharmacokinetics of SUVN-G3031 in healthy adult human volunteers.
P1-311
THE 5-HT6 ANTAGONIST SUVN-502 POTENTIATES THE EFFECTS OF ACETYLCHOLINESTERASE INHIBITORS ON EXTRACELLULAR ACETYLCHOLINE LEVELS AND IN ANIMAL MODELS OF COGNITION
Gopinadh Bhyrapuneni, Vijay S. Benade, Venkatesh Kamuju, Ranjith Kumar Ponnamaneni, Shantaveer M. Irappanavar, Pradeep Jayarajan, Renny Abraham, Laxman Kota, Sangram Keshari Saraf, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: SUVN-502 is a potent and selective 5-HT6 antagonist being developed for the symptomatic treatment of Alzheimer’s disease. SUVN-502 is orally bioavailable and has adequate brain penetration. SUVN-502 exhibited pro-cognitive properties when tested in various rodent models. In rat brain microdialysis, SUVN-502 increased acetylcholine levels in brain regions involved in learning and memory, providing the neurochemical basis for the pro-cognitive effects in rodent models. Methods: SUVN-502 alone and in combination with acetylcholinesterase inhibitors (donepezil or rivastigmine) was evaluated in object recognition task. Effect of