Broad analgesic activity of a novel, selective M1 agonist

  title={Broad analgesic activity of a novel, selective M1 agonist},
  author={Michael W. Wood and Giovanni Martino and Martin Coupal and Mattias Lindberg and Patricia E. Schroeder and Vijayaratnam Santhakumar and Manon Valiquette and Johan Sandin and Daniel V. Widzowski and Jennifer M. A. Laird},
&NA; Although the muscarinic receptor family has long been a source of potentially compelling targets for small molecule drug discovery, it was difficult to achieve agonist selectivity within the family. A new class of M1 muscarinic agonists has emerged, and these compounds have been characterized as agonists that activate the receptor at an allosteric site. Members of this class of M1 agonists have been shown to be selective across the muscarinic receptors. However, upon introduction of a… Expand
3 Citations
G-Protein Coupled Receptors Targeted by Analgesic Venom Peptides
The current state of knowledge regarding venom peptides that target GPCRs to produce analgesia, and their development as therapeutic compounds are reviewed. Expand
The muscarinic agonist pilocarpine modifies cocaine-reinforced and food-reinforced responding in rats: comparison with the cholinesterase inhibitor tacrine.
Overall, pilocarpine exhibited modest selectivity for attenuating self-administration of low-dose cocaine without affecting a nondrug reinforcer. Expand


Novel Selective Allosteric Activator of the M1 Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats
Characterization of a novel highly selective agonist for the M1 receptor with no agonist activity at any of the other mAChR subtypes, termed TBPB, and data suggest that selective activation of M1 may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease. Expand
Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100
It is reported that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice, and the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia is supported. Expand
Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice.
  • J. Gomeza, H. Shannon, +6 authors J. Wess
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1999
The M2 muscarinic receptor subtype, besides its well documented involvement in the regulation of heart rate, plays a key role in mediating muscaric receptor-dependent movement and temperature control as well as antinociceptive responses, three of the most prominent central muscarinate effects. Expand
Selective muscarinic receptor agonists and antagonists.
Novel, selective agonists and antagonists, both in terms of their use in defining muscarinic receptor subtypes and their potential clinical utility are assessed, to provide an advance over earlier therapeutics with which the clinical efficacy was compromised by the side effect profile. Expand
Xanomeline: a novel muscarinic receptor agonist with functional selectivity for M1 receptors.
The present data are consistent with the interpretation that xanomeline is a novel muscarinic receptor agonist with functional selectivity for M1 mus carinic receptors both in vitro and in vivo. Expand
Discovery of an ectopic activation site on the M(1) muscarinic receptor.
The finding that receptors for small-molecule transmitters can have multiple, structurally distinct activation sites has broad implications for the study of receptor structure/function and the potential for the discovery of novel ligands with high selectivity. Expand
Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists.
Results suggest that the newer compounds may have a greater clinical safety profile, especially with regard to muscarinic M(3) receptor-mediated events, than the historical agonists, but their affinities for other receptors may still compromise their use to validate the therapeutic potential of muscaric M(1) receptor agonists. Expand
The M1/M4 preferring agonist xanomeline is analgesic in rodent models of chronic inflammatory and neuropathic pain via central site of action
Testing xanomeline together with nonselective (scopolamine and pirenzepine), and selective (MT‐7 and MT‐3) muscarinic receptor (M1 and M4, respectively) antagonists in a number of inflammatory and neuropathic pain models suggested that the activation of supraspinal M1 receptors, and to a lesser extent suprasinal M4 receptors, contributes to that analgesia. Expand
Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice.
It is shown that muscarinic analgesia is exclusively mediated by a combination of M(2) and M(4) mAChRs at both spinal and supraspinal sites, and this finding should be of considerable relevance for the development of receptor subtype-selectiveMuscarinic agonists as novel analgesic drugs. Expand
Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77‐LH‐28‐1
The advent of functional screening assays has enabled the identification of agonists such as AC‐42, which bind to an allosteric site and selectively activate the M1 mAChR subtype, however, studies with this compound have been limited to recombinantly expressed mA ChRs. Expand