Vedaclidine (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

, codenamed LY-297,802, NNC 11-1053) is an experimental

analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhal ...

which acts as a mixed

agonist–antagonist In pharmacology the term agonist-antagonist or mixed agonist/antagonist is used to refer to a drug which under some conditions behaves as an agonist (a substance that fully activates the receptor that it binds to) while under other conditions, beha ...

muscarinic acetylcholine receptors Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rece ...

, being a potent and selective

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

for the M₁ and M₄ subtypes, yet an antagonist at the M₂, M₃ and M₅ subtypes. It is orally active and an effective analgesic over 3× the potency of

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. Ther ...

, with side effects such as

salivation Saliva (commonly referred to as spit) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which DNA can b ...

and

tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, f ...

only occurring at many times the effective analgesic dose. Human trials showed little potential for development of dependence or abuse, and research is continuing into possible clinical application in the treatment of

neuropathic pain Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli ( allodynia). It may have continuo ...

and

cancer pain Pain in cancer may arise from a tumor compressing or infiltrating nearby body parts; from treatments and diagnostic procedures; or from skin, nerve and other changes caused by a hormone imbalance or immune response. Most chronic (long-lasting) pai ...

relief.

Synthesis

: The

Knoevenagel condensation In organic chemistry, the Knoevenagel condensation () reaction is a type of chemical reaction named after German chemist Emil Knoevenagel. It is a modification of the aldol condensation. A Knoevenagel condensation is a nucleophilic addition of ...

between 3-Quinuclidone 731-38-2(1) &

ethyl cyanoacetate Ethyl cyanoacetate is an organic compound that contains a carboxylate ester and a nitrile. It is a colourless liquid with a pleasant odor. This material is useful as a starting material for synthesis due to its variety of functional groups and che ...

05-56-6(2) gives Ethyl (1-azabicyclo .2.2ctan-3-ylidine)cyanoacetate
CID:54445383
(3). The

catalytic hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organic c ...

of the olefin group gave Ethyl (1-azabicyclo .2.2ctan-3-yl)cyanoacetate 41593-50-2(4). The reaction with sodium in ethanol, followed by addition of isoamylnitrite 10-46-3led to (1-Azabicyclo .2.2ctan-3-yl)hydroxyiminoacetonitrile
CID:73192825
(5). Halogenation with

Disulfur dichloride Disulfur dichloride is the inorganic compound of sulfur and chlorine with the formula S2Cl2. Some alternative names for this compound are ''sulfur monochloride'' (the name implied by its empirical formula, SCl), ''disulphur dichloride'' (British ...

0025-67-9in DMF gave 3-(3-Chloroquinuclidine-3-yl)-4-chloro-1,2,5-thiadiazole
CID:9795252
(6). :

Catalytic hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organic c ...

went on to give 3-Chloro-4-quinuclidin-3-yl-1,2,5-thiadiazole
CID:9942707
(7). : The reaction with sodium hydrogen sulfide in the presence of potassium carbonate, followed by addition of

1-bromobutane 1-Bromobutane is the organobromine compound with the formula CH3(CH2)3Br. It is a colorless liquid, although impure samples appear yellowish. It is insoluble in water, but soluble in organic solvents. It is a primarily used as a source of the buty ...

completed the synthesis of ''Vedaclidine'' (8).

References

{{Muscarinic acetylcholine receptor modulators Analgesics Muscarinic agonists Muscarinic antagonists Quinuclidines Thiadiazoles Thioethers Experimental drugs Butyl compounds

Synthesis

See also

References