An “agonist” mimics or promotes the action of something else. Several new NAChR drugs are coming onto the market to treat neuropathic pain.
Hopefully you read the prior article on nicotine. If so, you know that ACh (acetyl choline, which binds ionotropically with nicotinic and metabotropically with muscarinic receptors of the autonomic nervous sytem) acts as a ligand or tie to the nicotinic receptors. Agonists similar to it are being sought to enhance a descending pain inhibitory pathway. Other chemicals can also act as ligands for the nAChRs and some may have use in neuropathic pain.
Marshall Devor has been most gracious to review topics and suggest ideas which have been valuable for articles at this site. His discovery of a formerly unknonwn descending inhibitory pain tract in the the rostral ventral medulla (see Devor using SEARCH at this site) led to increased interest in cholinergic compounds, which link to serotonin.
See also Bunnelle and Decker, writing in Expert Opinion on Therapeutic Patents, Volume 13, Number 7, 1 July 2003, pp. 1003-1021(19
The authors attempted to point out the difference between NEURONAL nicotinic receptors and those associated with the neuromuscular juntion. Our concerns would be for drugs aimed at the neuron, not the muscle cell. We also do not want to upset autonomic function, especially in SCI patients, with any drugs. The 42 subtype of the nAChR attenuates acute thermal pain. the 34 subtype regulates the autonomics. However, recent work shows that there are actually seven subtypes involved with pain and inflammation. This assumption is based on the discovery of seven ligands which work.
There are active new patent aoplications for new ligand subtypes being developed. The biological data in patent applications is very sparse to protect intellectual property and corporate research secrets, so we are not certain how potent these things are. Some of the companies are spending a lot of money to get them through the FDA so we presume the company heads believe in them. The idea is to enhance the descending pain inhibitory pathway which is mediated by nAChRs. Epibatidine, one of the early drugs along this line, a drug which is very toxic, was said to be two hundred times more potent than morphine. The idea was to find an nAChR which fired up the neuronal nicotinic ACh receptor and left the autonomic and neuromuscular receptors untouched. So, the whole thing gets interesting.
Decker, et al, working for Abbott, wrote one of the early pieces, Expert Opin Investig Drugs (2001) 10: 1819-30. and stated that while the archtypical nAChR agonist, epibatidine, had fatal side effects, potent NEW agonists with anti-nociceptive effects were on the way. He highlighted ABT 594, which was a nicotinic agonist, and pointed out that evidence suggested it was acting on a descending inhibitory pathway. and reported that in the brain, the alpha4beta2 subtype was the paramount nicotinic receptor relating to pain inhibition, presumably linking with a tract which began in the brainstem. These authors felt that ABT 594 might well have a role in “pathologic pain”.
Kiesingland, et al in Pain. 2000 May;86(1-2):113-8 reported that both epibatidine and ABT 594 reduced inflammatory and neuropathic hyperalgesia at doses below that which would disturb locomotor action. This suggested that a therapeutic window did in fact exist.
Donnelly-Roberts et al in J Pharmacol Exp Ther. 1998 May;285(2):777-86 had already identified ABT-594 as the chemical [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine], which can be given ORALLY. They found that ABT-594 was a potent inhibitor of the binding of [3H](-)-cytisine to alpha 4 beta 2 neuronal nAChR. They also showed that ABT-594 inhibits the release of calcitonin gene-related peptide (CGRP) from C-fibers terminating in the dorsal horn of the spinal cord, an effect mediated via nAChRs. You can read about CGRP in the prior article and elsewhere at this site. CGRP is a pain chemical.
Boyce et al at Merck, writing in Pain. 2000 Apr;85(3):443-50 confirmed the antinoiception of ABT 594 but reported some hypothermia and seizures. It appeared we were not home yet on nAChRs.
Lawand et al in Pain. 1999 Mar;80(1-2):291-9 had found that pain from arthritic inflammation seemed to originate from nicotinic activity in the dorsal horn of the cord.
And so, these pro and con articles kept the interest up, with everyone looking for the right ligand to make it all work for neuropathic pain.
Metabolic Pharmaceuticals may now have found an answer with ACV 1, a new drug, an nAChR agonist, entering phase 2 Human trials. The scant information coming from comments indicates that side effects may be minimal and it may work. We are watching this area and encourage you to do the same. Please report to us any experience you may have had with ACV 1(using COMMENTS).