Abstract |
Diversification of essential nicotinic cholinergic pharmacophoric elements, i.e., cationic center and hydrogen bond acceptor, resulted in the discovery of novel potent α4β2 nAChR selective agonists comprising a series of N-acyldiazabicycles. Core characteristics of the series are an exocyclic carbonyl moiety as a hydrogen bond acceptor and endocyclic secondary amino group. These features are positioned at optimal distance and with optimal relative spatial orientation to provide near optimal interactions with the receptor. A novel potent and highly selective α4β2 nAChR agonist 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0] octane (56, TC-6683, AZD1446) with favorable pharmaceutical properties and in vivo efficacy in animal models has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions and is currently being progressed to phase 2 clinical trials as a treatment for Alzheimer's disease.
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Authors | Anatoly A Mazurov, Lan Miao, Balwinder S Bhatti, Jon-Paul Strachan, Srinivasa Akireddy, Srinivasa Murthy, David Kombo, Yun-de Xiao, Philip Hammond, Jenny Zhang, Terry A Hauser, Kristen G Jordan, Craig H Miller, Jason D Speake, Gregory J Gatto, Daniel Yohannes |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 55
Issue 21
Pg. 9181-94
(Nov 08 2012)
ISSN: 1520-4804 [Electronic] United States |
PMID | 22793665
(Publication Type: Journal Article)
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Chemical References |
- 3-(5-chloro-2-furoyl)-3,7-diazabicyclo(3.3.0)octane
- Bridged Bicyclo Compounds, Heterocyclic
- Nicotinic Agonists
- Receptors, Nicotinic
- nicotinic receptor alpha4beta2
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Topics |
- Animals
- Brain
(metabolism)
- Bridged Bicyclo Compounds, Heterocyclic
(chemical synthesis, chemistry, pharmacology)
- Cell Line
- Cognition Disorders
(drug therapy)
- Cricetinae
- Cricetulus
- Exploratory Behavior
(drug effects)
- Humans
- Male
- Models, Molecular
- Nicotinic Agonists
(chemical synthesis, chemistry, pharmacology)
- Rats
- Rats, Sprague-Dawley
- Receptors, Nicotinic
(metabolism)
- Stereoisomerism
- Structure-Activity Relationship
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