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P1‐077: IN‐VITRO CHARACTERIZATION OF SUVN‐I2004: A NOVEL MUSCARINIC M 1 POSITIVE ALLOSTERIC MODULATOR
Author(s) -
Subramanian Ramkumar,
Mekala Venkat Reddy,
Srirangavaram Maheswari,
Mary Praveeissankararao,
Edula Surekha,
Petlu Surendra,
Irappanavar Shantaveer M.,
Rasheed Mohammed Abdul,
Nirogi Ramakrishna
Publication year - 2018
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.2018.06.079
Subject(s) - muscarinic acetylcholine receptor , pharmacology , muscarinic acetylcholine receptor m5 , muscarinic acetylcholine receptor m1 , muscarinic acetylcholine receptor m4 , agonist , allosteric modulator , chemistry , cholinergic , allosteric regulation , muscarinic acetylcholine receptor m3 , receptor , neuroscience , biology , biochemistry
Background: Muscarinic agonist xanomeline, though efficacious has not been used in the treatment of dementia associated with Alzheimer’s disease due to its side effect profile. The current strategy is to target the allosteric site to circumvent the side effects while retaining the efficacy. SUVN-I2004 is one of our lead compounds that have been thoroughly profiled. Current presentation covers SUVN-I2004 in-vivo efficacy and safety. Methods: SUVN-I2004 was tested for its efficacy in the object recognition task (ORT) both in time induced memory deficit and scopolamine induced memory deficit versions of the task. The effect of SUVN-I2004 on cerebral blood flow was assessed as well. The effect on the modulation of soluble amyloid precursor protein-a (sAPP-a) was studied in rat cortex. Effect on the neuronal oscillations and acetylcholine modulation in rats were evaluated in combination with donepezil. The modulation of inositol phosphate 1 (IP1) in striatum by SUVN-I2004 was evaluated in male Swiss Albino mice. SUVN-I2004 was profiled extensively for cholinergic side effects both in rats and dogs. Cardiovascular safety of SUVN-I2004 was assessed using guinea pigs. SUVN-I2004 was also evaluated in general toxicity and genotoxicity assays. Results: SUVN-I2004 increased cerebral blood flow and exhibited procognitive properties in both version of the ORT. SUVN-I2004 produced significant and dose dependent increase in cortical sAPP levels in rats. Combined administration of SUVN-I2004 and donepezil produced acetylcholine levels and power in evoked theta that were significantly higher compared to donepezil alone. Acute administration of SUVNI2004 produced dosedependent increase in striatal IP1 levels at doses several fold higher than therapeutically meaningful doses. No signs of cholinergic effects were observed in rats or dogs at the tested doses. SUVN-I2004 had no effect on QTc or heart rate in guinea pigs.SUVN-I2004 was non-mutagenic in AMES assay and has a good safety margin. Conclusions: SUVN-I2004 was found to be devoid of cholinergic side effects associated with earlier M1PAMs or muscarinic agonists. SUVN-I2004 exhibited procognitive properties.