title: Two novel α7 nicotinic acetylcholine receptor ligands: in vitro properties and their efficacy in collagen-induced arthritis in mice.
abstract: BACKGROUND
  The cholinergic anti-inflammatory pathway can downregulate inflammation via the release of acetylcholine (ACh) by the vagus nerve. This neurotransmitter binds to the α7 subunit of nicotinic acetylcholine receptors (α7nAChR), expressed on macrophages and other immune cells. We tested the pharmacological and functional profile of two novel compounds, PMP-311 and PMP-072 and investigated their role in modulating collagen-induced arthritis (CIA) in mice.
  
  
  METHODS
  Both compounds were characterized with binding, electrophysiological, and pharmacokinetic studies. For in vivo efficacy studies in the CIA model the compounds were administered daily by oral gavage from day 20 till sacrifice at day 34. Disease progression was monitored by visual clinical scoring and measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology.
  
  
  RESULTS
  Treatment with PMP-311 was effective in preventing disease onset, reducing clinical signs of arthritis, and reducing synovial inflammation and bone destruction. PMP-072 also showed a trend in arthritis reduction at all concentrations tested. The data showed that while both compounds bind to α7nAChR with high affinity, PMP-311 acts like a classical agonist of ion channel activity, and PMP-072 can actually act as an ion channel antagonist. Moreover, PMP-072 was clearly distinct from typical competitive antagonists, since it was able to act as a silent agonist. It synergizes with the allosteric modulator PNU-120596, and subsequently activates desensitized α7nAChR. However, PMP-072 was less efficacious than PMP-311 at both channel activation and desensitization, suggesting that both conducting and non-conducting states maybe of importance in driving an anti-inflammatory response. Finally, we found that the anti-arthritic effect can be observed despite limited penetration of the central nervous system.
  
  
  CONCLUSIONS
  These data provide direct evidence that the α7nAChR in immune cells does not require typical ion channel activation to exert its antiinflammatory effects.
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marjolein A
authors.initials: MA
authors.lastname: van Maanen
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida, United States of America.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Frieda A
authors.initials: FA
authors.lastname: Koopman
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands; Arthrogen BV, Amsterdam, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Koepke
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands; Arthrogen BV, Amsterdam, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: Bevaart
authors.affiliation: Cornerstone Therapeutics, Inc., Cary, North Carolina, United States of America.
authors.forename: Roger
authors.initials: R
authors.lastname: Clark
authors.affiliation: Cornerstone Therapeutics, Inc., Cary, North Carolina, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Lamppu
authors.affiliation: DEC Associates, LLC, Newton, Massachusetts, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Elbaum
authors.affiliation: Cornerstone Therapeutics, Inc., Cary, North Carolina, United States of America.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: LaRosa
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands; Arthrogen BV, Amsterdam, The Netherlands.
authors.forename: Margriet J
authors.initials: MJ
authors.lastname: Vervoordeldonk
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D002460:Cell Line; D007249:Inflammation / Q000188:drug therapy; D007719:Knee Joint / Q000187:drug effects / Q000473:pathology; D008024:Ligands; D051379:Mice; D008815:Mice, Inbred Strains; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D000813:Anilides; D008024:Ligands; D010080:Oxazoles; C000604715:PMP-072; C000604714:PMP-311; D010879:Piperazines; D011725:Pyridines; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000109:Acetylcholine