Cembranoid inhibitors of nicotinic acetylcholine receptors

Details Cembranoid inhibitors of nicotinic acetylcholine receptors Cembranoid inhibitors of nicotinic acetylcholine receptors

1998-06-04

2001-03-20

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S460000, C514S461000, C514S470000, C514S475000, C514S813000

Reexamination Certificate

active

06204289

ABSTRACT:

BACKGROUND OF THE INVENTION
Nicotinic acetylcholine receptors (AchRs) are proteins that control skeletal muscle contraction, sympathetic and parasympathetic ganglia function (which is related to the control of the cardiovascular and visceral functions) and important communication pathways in the brain. These receptors are disturbed in the Alzheimer's and Parkinson's diseases, schizophrenia and other disorders involving memory loss, cognitive problems and/or dementia (2,14,15). Neuronal AchRs are the biological substrate for nicotine addiction (3-6, 17). Blockade of these receptors could contribute to the anti-addictive properties of certain alkaloids (1).
Inhibitors of AchRs affect all these processes and many are used for therapeutic purposes. These inhibitors form a large, chemically-heterogenous group of compounds, which block the receptor by a variety of mechanisms (15).
We discovered a new family of AchR inhibitors, the cembranoids isolated from gorgonian corals (see the ‘Detailed Description of the Invention’). Some aspects of this discovery were reported in the literature (7-13, 16, 18, 19).
To our knowledge, there are no other patents related to the use of cembranoids as inhibitors of AChRs.
SUMMARY OF THE INVENTION
Cembranoids are cyclic diterpenoids naturally present in many plants and invertebrate animals. We discovered that cembranoids inhibit both peripheral and neuronal AchRs at concentrations ranging from 10
−15
molar to 10
−4
molar; cembranoids also increase the rate of receptor desensitization. Seventeen different cembranoid analogs were tested. There are two main differences between previously known AchR inhibitors and these new cembranoid inhibitors. First, two of the new inhibitors (eupalmerin acetate and pseudoplexauric acid) are more potent than any previously known inhibitors by a factor of at least 1000; therefore, less side effects would be expected in any potential therapeutic application. Second, cembranoids are present in tobacco leaves, and therefore potentially have an effect on nicotine action in the brains of cigarette smokers. Nicotine-induced desensitization of neuronal acetylcholine receptors is related to behavioral tolerance or addiction to nicotine (6); since cembranoids increase receptor desensitization, they are likely to increase tobacco addictive properties. Thus, by extracting the cembranoids from tobacco, this could produce less addictive cigarettes (or any tobacco related product). On the other hand, addition of cembranoids to tobacco could possibly increase its addictive properties. In addition, cembranoids displace general anesthetics from the muscle-type AchR, and so they could ameliorate the undesirable side-effects of anesthesia in patients with Myasthenia gravis.


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