Mohammed Abdul Rasheed

Antinociceptive activity of α4β2* neuronal nicotinic receptor agonist A-366833 in experimental models of neuropathic and inflammatory pain

Nerve injury, diabetes and cancer therapies are often associated with painful neuropathy. The mechanism underlying neuropathic pain remains poorly understood. The current therapies have limited efficacy and are associated with dose-limiting side effects. Compounds which act at nicotinic acetylcholine receptors have also been reported to show antinociceptive activity. Among those, tebanicline (ABT-594) a potent nicotinic acetylcholine receptor agonist demonstrated analgesic effects across a broad range of preclinical models of nociceptive and neuropathic pain. Another nicotinic acetylcholine receptor agonist, 5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) from the same group produced significant antinociceptive effects in writhing pain (abdominal constriction), acute thermal pain (hot box), persistent chemical pain (formalin induced) and neuropathic pain. In the present study, we have demonstrated the efficacy of A-366833 in rat models of chronic constriction injury, partial sciatic nerve ligation, spinal nerve ligation, diabetes, chemotherapy induced neuropathic pain and complete Freunds adjuvant induced inflammatory pain. A-366833 (1, 3 and 6 mg/kg) produced significant antihyperalgesic effects in partial sciatic nerve ligation, chronic constriction injury and spinal nerve ligation models. In the diabetic and chemotherapy induced neuropathic models compound exerted antinociceptive activity and reduction in the mechanical hyperalgesia was observed. A-366833 dose dependently attenuated mechanical hyperalgesia in complete Freunds adjuvant induced inflammatory pain model. These results demonstrated broad-spectrum antinociceptive properties of A-366833 in both neuropathic and inflammatory pain models.

In-vivo rat striatal 5-HT4 receptor occupancy using non-radiolabelled SB207145

The objective of the current investigation was to develop a simple, rapid method for determining in‐vivo 5‐hydroxytryptamine type 4 receptor (5‐HT4R) occupancy in rat brain using non‐radiolabelled SB207145 as a tracer for accelerating the drug discovery process.

Suvn-d4010: A novel 5-ht4 receptor partial agonist for the treatment of Alzheimer’s disease

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder of advanced age characterized by loss of memory, accumulation of amyloid beta protein (Ab) deposits and decreased levels of the neurotransmitter acetylcholine. 5-HT4 receptor partial agonists may be of benefit for both the symptomatic and disease-modifying treatment for AD and may offer improved clinical efficacy and/or tolerability relative to acetylcholine esterase inhibitors. Methods: SUVN-D4010 a potent, selective and orally bioavailable 5-HT4 partial agonist was evaluated for its procognitive properties in object recognition task, radial arm maze task and fear conditioning assay. Modulation of acetylcholine levels by SUVN-D4010 was evaluated using brain microdialysis technique. Striatal 5-HT4 receptor occupancy was measured using non-radiolabeled tracer in rats. Cortical sAPPa levels and CSF amyloid-b protein levels were also evaluated in the preclinical species using ELISA kits. Safety, general toxicity and mutagenic potential of SUVN-D4010 were evaluated in rodents/non rodents and in-vitro models. Results: SUVN-D4010 reversed the episodic memory deficits in object recognition task, 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 observed was blocked by a selective 5-HT4 antagonist. SUVN-D4010 showed a dose dependent increase in receptor occupancy in rat brain. A significant increase in cortical sAPPa and decrease in CSF amyloid-b protein levels was noted in non-transgenic animal models. SUVN-D4010 was well tolerated in animal toxicity studies and did not show any mutagenic potential in-vitro.Conclusions: SUVN-D4010 is a novel, potent, selective, orally bio-available, efficacious and safe 5-HT4 receptor partial agonist. IND enabling studies are completed and US IND filing is in progress.

Concise and Simple Synthesis of M1 Allosteric Agonist TBPB

Abstract A concise and simple synthesis of M1 allosteric agonist 1-(1′-(2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (TBPB) using economical and commercially available orthophenylenediamine (O-PDA) and Boc piperidone has been described. The disclosed scheme allows synthesizing more analogs that were otherwise difficult to prepare with the original method. Supplemental materials are available for this article. Go to the publishers online edition of Synthetic Communications® to view the free supplemental file. GRAPHICAL ABSTRACT

SUVN-M8036, A SEROTONERGIC AND DOPAMINERGIC MODULATOR, ALLEVIATES PSYCHOSIS AND DEPRESSION

predicting ReHo from cumulative SBP and DBP adjusted for age, sex and race. Results: Greater SBP was associated with lesser ReHo in the bilateral hippocampi, left insula, right lingual, precentral and middle temporal gyri. Greater DBP was associated with lesser ReHo in the bilateral hippocampi, lingual and superior temporal gyri and brainstem and the left temporal pole, right frontal pole and inferior frontal gyrus. Greater DBP was also associated with greater ReHo in the left frontal pole. Conclusions:Greater cumulative BP exposure during young adulthood through midlife is associated with lesser local connectivity in various brain regions linked to cognitive performance, in particular, bilateral hippocampi. The link between BP and hippocampal connectivity is particularly intriguing in the context of established impact of cardiovascular risk factors on Alzheimer’s disease.

IN-VITRO CHARACTERIZATION OF SUVN-I2004: A NOVEL MUSCARINIC M1 POSITIVE ALLOSTERIC MODULATOR

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.

SUVN-D4010: A POTENT AND SELECTIVE 5-HT 4 RECEPTOR PARTIAL AGONIST— ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS

of the depositions, 6E10-positive depositions were observed torus-like shapes with having relatively strongly immunoreactive cores, and m6H4-positive depositions existed inhomogeneous granular shapes. Conclusions: Ab oligomer depositions possibly grow according to the increase of Ab depositions, but its immunoreactivity was different from those of senile plaques. References: 1. Saito T, et al. Nat Neurosci 2014; 17(5): 661–3. 2. Takamura A, et al. Mol Neurodegener 2011;6(1):20.

Suvn-i1312004, a novel m1 muscarinic acetylcholine receptor-positive allosteric modulator: Potential for the treatment of Alzheimer’s disease

of platform were reduced significantly in 1 month old 5XFAD mice compared to the wild type mice. The percentage of aberrant myelinated axons and g-ratio were increased significantly, while the protein of myelin were also changed. The DTI also detected the changes of fractional anisotropy (FA), mean diffusivity (MD), axonal diffusivity (DA) and radial diffusivity (DR) in the key brains of cognitive circuit such as hippocampus (hippo), retrosplenial cortex (RsC/Rsg), prefrontal cortex (PFC) and entorhinal cortex (Ent). The change of LINGO-1 protein in key brain areas related to cognition was also detected. Therefore, the LINGO-1 antibody was administrated at the end of 1 month. The spatial memory of 5XFAD could be recovery at 3 month (Fig. 1). In addition, the ultra structure of myelin (Fig. 2) and myelin protein (Fig. 3) were also recovered accompanied by the changes of the four parameters of DTI (Fig. 4). Conclusions: Hippocampus-based memory was impaired in 5XFAD mice and deteriorated with age, which could be related to demyelination at the early stage. Blocking LINGO-1 could restore the impairements of myelin partly, improve the memorial function, and may be a new therapeutic target for AD in the early stage.

IN VIVO BRAIN RECEPTOR OCCUPANCY FOR PDE-10 RECEPTORS IN MICE AND RATS USING NON-RADIOLABELED TRACER

Background:Archival neuropathologicmaterialmayprove to bevery useful andmay significantly aid the neurologist in the diagnosis of hereditary neurodegenerative disease. The fixed and paraffin embedded brain tissue of a 33year-old woman has been studied and archived since 1991. The proband’s son presented with neurological signs 22 years after the proband’s death. Methods: Clinical and family reports detailing the evolution of the proband’s illness were available. Neuropathologic studies of the brain, postmortem, had been carried out using histological methods including hematoxylin and eosin with Luxol fast blue (H&E/LFB), Bielschowsky and Thioflavin S. For immunohistochemistry, antibodies against tau, and amyloid beta (Ab) were used. DNA could not be extracted from fixed tissue, but was obtained from the 27-year-old son of the proband. Results:While in high school, the proband showed forgetfulness, loss of coordination and some trouble walking. During college, she required tutoring. At age 28, following the birth of her first child, she became progressively ataxic. By age 30, she was no longer able towalk without the aid of a walker. She had difficulty in speaking and swallowing. Neurologic exam at age 31 showed severe spastic and ataxic gait and significant memory loss. Extensive diagnostic work-up was negative. A magnetic resonance imaging study revealed decreased signal in the putamen and globus pallidus. Multiple sclerosis, spinocerebellar degeneration and Hallervorden-Spatz disease were considered as possible diagnoses. The patient deteriorated rapidly and died at the age of 33. Three neuropathologists, independently, diagnosed the proband as having been affected by Alzheimer disease. The 27-year-old proband’s son presented with hyperreflexia, dysarthria, and gait abnormalities. Molecular genetic analysis revealed anATG>GTGpoint mutation predicting an amino acid substitution of methionine to valine (M233V) in the PSEN1 gene. Conclusions: Considering the similarity of the clinical presentation and the age of onset of symptoms in the proband and her son, we hypothesize that both individuals have the PSEN1 M233V mutation and that the son is in the very early stage of familial Alzheimer disease. The data from the archival tissue contributed significantly to direct toward a diagnosis and a potential therapeutic interventions for the proband’s son. Funding source: P30AG010133.

Corrigendum to “Antinociceptive activity of α4β2* neuronal nicotinic receptor agonist A-366833 in experimental models of neuropathic and inflammatory pain” [Eur. J. Pharmacol. 668 (2011) 155–162]

Corrigendum to “Antinociceptive activity of α4β2* neuronal nicotinic receptor agonist A-366833 in experimental models of neuropathic and inflammatory pain” [Eur. J. Pharmacol. 668 (2011) 155–162] Ramakrishna Nirogi ⁎, Pradeep Jayarajan, Renny Abraham, Dhanalakshmi Shanmuganathan, Mohammed Abdul Rasheed, Praveen Kumar Royapalley, Venkatesh Goura a Department of Pharmacology, Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road No. 5, Avenue-7, Banjara Hills, Hyderabad, 500034, India b Department of Medicinal Chemistry, Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road No. 5, Avenue-7, Banjara Hills, Hyderabad, 500034, India