Nicotinic Ligands as Smoking Cessation Agents

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$577,800.00
Award Year:
2007
Program:
STTR
Phase:
Phase I
Contract:
1R41DA023291-01
Award Id:
85506
Agency Tracking Number:
DA023291
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
*(FY 08 USE 4147301), TARRYTOWN, NY, 10591
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
n/a
Principal Investigator:
WERNER TUECKMANTEL
() -
Business Contact:
() -
Research Institution:
UNVERSITY OF MISSISSIPPI MEDIC

UNIVERSITY OF MISSISSIPPI
100 BARR HALL
UNIVERSITY, MS, 38677

Nonprofit college or university
Abstract
DESCRIPTION (provided by applicant): Tobacco use and nicotine addiction are an immense burden on the public health. There are an estimated 44.5 million (21%) adult smokers and an estimated 3.75 million (22%) high school student smokers in the US. Tobacco u se is responsible for over 440,000 deaths per year in the US, which accounts for 1 in every 5 total deaths. Approximately 70% of the adult smokers want to quit. However, only 5-10% succeeds each year. Their inability to quit, even with full understanding o f the negative health consequences, is testament to the addicting power of nicotine. Numerous studies showed that neuronal nicotinic acetylcholine receptors (nAChRs) are major mediators in brain for the development of addiction to smoking. Among major nACh R subtypes in brain, nAChRs containing both a4 and a2 subunits are essential for nicotine addiction. The current leading treatment for nicotine addiction is nicotine replacement therapy. However, with meager success rates of 10-20%, new therapies are great ly needed. Very recently, Pfizer's Chantix(r) (varenicline) was approved by the FDA as a smoking cessation drug. Varenicline is a partial agonist at the a4a2 nAChR subtype. Clinical trials showed that varenicline helped up to 45% of smokers stay smoke free for up to 12 weeks. This result validates the a4a2 subtype as a target for smoking cessation. However, varenicline has almost full agonist activity at the a3a4 and a7 subtypes, which may lead to side effects such as nausea seen in 30% of the patients. For any disease state as prevalent as nicotine addiction, it is essential to have a number of treatment options. Acenta Discovery and its collaborators have embarked on the goal to develop alternative a4a2-selective nAChR ligands as a treatment for smoking ce ssation. A series of such ligands have previously been prepared that bear at C3 of their pyridine ring an azetidine or pyrrolidine connected through a CH2O linker, and a lipophilic side chain on C5. Many of these ligands are very potent and selective. One lead, sazetidine-A, exhibits subnanomolar binding affinity and gt104-fold selectivity for the a4a2 over the ganglionic a3a4 subtype. Pharmacologically, sazetidine-A is quite novel as a 'silent desensitizer'. It desensitizes a4a2 nAChRs without activating t hem and maintains them in their desensitized state. Functional assays revealed that sazetidine-A, in contrast to varenicline, does not show agonist activity at either the a4a2 or a3a4 nAChR subtypes. Notably, initial work in animals revealed that it also h as nicotine-like discriminative stimulus effects. With this unique lead compound, we would like the opportunity to study in more detail the SAR for sazetidine-A. The goals of this proposal are: (1) design and synthesize a series of sazetidine-A analogs bas ed on preliminary data; (2) assay the analogs for binding and function with an array of nAChR subtypes; (3) select the most promising analogs for nicotine discrimination animal experiments. Ideally, this work will lead into the development of new a4a2 subt ype selective nicotinic ligands to be used for smoking cessation therapy.

* information listed above is at the time of submission.

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