title: α4β2 neuronal nicotinic receptor positive allosteric modulation: an approach for improving the therapeutic index of α4β2 nAChR agonists in pain.
abstract: Nicotinic acetylcholine receptors (nAChRs) function as ligand-gated ion channels activated by the neurotransmitter acetylcholine. Gene knockout and antisense studies coupled with pharmacological studies with nAChR agonists have documented a role of α4β2 nAChR activation in analgesia. ABT-594, for the first time, provided clinical validation to the nAChR agonist pharmacology as a novel mechanism for treatment of pain. However, ABT-594 was poorly tolerated at the efficacious doses, particularly with respect to the side effects of nausea and emesis, which is thought to be mediated by activation of the ganglionic-type (α3-containing) nAChRs. An alternate approach is to selectively modulate the α4β2 nAChR via positive allosteric modulation. Positive allosteric modulators (PAMs) are compounds that do not interact with the agonist binding sites or possess intrinsic activity at the receptor per se, but potentiate the effects of the agonist. NS9283 (also known as A-969933), the first oxadiazole analog, was found to selectively enhance the potency of a range of nAChR agonists at α4β2, but not α3β4, nAChRs. Studies reported here, along with the accompanying manuscript [1] collectively point to the conclusion, based on preclinical models, that the analgesic efficacy of clinically well-tolerated doses of ABT-594 in humans can be significantly enhanced by co-administration with the α4β2 PAM. Additionally, studies in ferrets demonstrate no exaggeration of emetic effect when ABT-594 is co-dosed with NS9283. Cardiovascular studies in anesthetized dogs achieve supra-therapeutic plasma concentrations of ABT-594 (>20-fold) without hemodynamic or electrophysiological effects using the co-administration paradigm.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA. lance.lee@abbott.com
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Chang
authors.initials: C
authors.lastname: Zhu
authors.forename: John
authors.initials: J
authors.lastname: Malysz
authors.forename: Thomas
authors.initials: T
authors.lastname: Campbell
authors.forename: Thomas
authors.initials: T
authors.lastname: Shaughnessy
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: James
authors.initials: J
authors.lastname: Polakowski
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D057809:HEK293 Cells; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D017116:Low Back Pain / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014839:Vomiting / Q000139:chemically induced
chemical_list: C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D000700:Analgesics; D001384:Azetidines; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D002118:Calcium