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    SURFE²R 96SE: 非标记高通量转运体筛选

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    Dynamic Clamp: Patchliner

  • 脂双层记录: Orbit产品系列

    脂双层记录: Orbit产品系列

  • CardioExcyte 96 SOL:用光遗传的手段起搏心肌细胞

    CardioExcyte 96 SOL:用光遗传的手段起搏心肌细胞

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SyncroPatch 384i

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SURFE²R N1

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Vesicle Prep Pro

2020 - Discovery and Development of SUVN-911: A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression

icon pl  Patchliner publication in Journal of Medicinal Chemistry (2020)

Authors:
Nirogi R., Mohammed A.R., Shinde A.K., Ravella S.R., Bogaraju N., Subramanian R., Mekala V.R., Palacharla R.C., Muddana N., Thentu J.B., Bhyrapuneni G., Abraham R., Jasti V.

 

Journal:
Journal of Medicinal Chemistry (2020) doi: 10.1021/acs.jmedchem.9b00790 (ahead of print)


Abstract: 

A series of chemical optimizations guided by in vitro affinity at the α4β2 receptor in combination with selectivity against the α3β4 receptor, pharmacokinetic evaluation, and in vivo efficacy in a forced swim test resulted in identification of 3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane hydrochloride (9h, SUVN-911) as a clinical candidate. Compound 9h is a potent α4β2 receptor ligand with a Ki value of 1.5 nM. It showed >10 μM binding affinity toward the ganglionic α3β4 receptor apart from showing selectivity over 70 other targets. It is orally bioavailable and showed good brain penetration in rats. Marked antidepressant activity and dose-dependent receptor occupancy in rats support its potential therapeutic utility in the treatment of depression. It does not affect the locomotor activity at doses several folds higher than its efficacy dose. It is devoid of cardiovascular and gastrointestinal side effects. Successful long-term safety studies in animals and phase-1 evaluation in healthy humans for safety, tolerability, and pharmacokinetics paved the way for its further development.


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