Search

Your search keyword '"Wood, Michael"' showing total 2 results
Start Over Author "Wood, Michael" Topic m1 Topic muscarinic receptors
2 results on '"Wood, Michael"'

1. Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: The continued optimization of an MLPCN probe molecule

Author

Poslusney, Michael S., Melancon, Bruce J., Gentry, Patrick R., Sheffler, Douglas J., Bridges, Thomas M., Utley, Thomas J., Daniels, J. Scott, Niswender, Colleen M., Conn, P. Jeffrey, Lindsley, Craig W., and Wood, Michael R.

Subjects
*ISATIN, *MUSCARINIC receptors, *MOLECULAR probes, *CYCLIC compounds, *SUBSTITUTION reactions, *KETONES, *STRUCTURE-activity relationships
Abstract

Abstract: This Letter describes the further optimization of an MLPCN probe molecule (ML137) through the introduction of 5- and 6-membered spirocycles in place of the isatin ketone. Interestingly divergent structure–activity relationships, when compared to earlier M1 PAMs, are presented. These novel spirocycles possess improved efficacy relative to ML137, while also maintaining high selectivity for the human and rat muscarinic M1 receptor subtype. [Copyright &y& Elsevier]

Published
2013
Full Text
View/download PDF

2. Further exploration of M1 allosteric agonists: Subtle structural changes abolish M1 allosteric agonism and result in pan-mAChR orthosteric antagonism

Author

Sheffler, Douglas J., Sevel, Christian, Le, Uyen, Lovell, Kimberly M., Tarr, James C., Carrington, Sheridan J.S., Cho, Hyekyung P., Digby, Gregory J., Niswender, Colleen M., Conn, P. Jeffrey, Hopkins, Corey R., Wood, Michael R., and Lindsley, Craig W.

Subjects
*MUSCARINIC receptors, *ALLOSTERIC regulation, *LIGANDS (Biochemistry), *MOLECULAR switches, *PHARMACOLOGY, *G protein coupled receptors
Abstract

Abstract: This letter describes the further exploration of two series of M1 allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M1 allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M1 allosteric agonist family (VU0357017) identified similar, subtle ‘molecular switches’ that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M1 activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism. [Copyright &y& Elsevier]

Published
2013
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results