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Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery.
TLDR
Allosteric modulation of GABAA by the benzodiazepine class has proven clinically safe and effective, and has now been developed for other ion channels, kinases, phospholipases and 7 Transmembrane Spanning Receptors (7TMRs). Expand
Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100
TLDR
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
"Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology.
TLDR
The impact of modest structural changes to multiple mGluR allosteric ligands scaffolds that unexpectedly modulate pharmacology are discussed and concerns over metabolism and the pharmacology of metabolites are raised. Expand
Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease.
TLDR
A survey of selected compounds in this area will be presented, with a focus on muscarinic agonists that display improved selectivity for this receptor by targeting allosteric modes of receptor activation. Expand
Muscarinic receptor pharmacology and circuitry for the modulation of cognition.
TLDR
The muscarinic cholinergic circuitry and pharmacology of mAChR agonists and antagonists relevant to the modulation of different aspects of cognition in animals and clinical populations are reviewed. Expand
Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071.
TLDR
From this, VU0364572 emerged as a potent, orally bioavailable and CNS penetrant M(1) agonist with high selectivity, clean ancillary pharmacology and enantiospecific activity. Expand
Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354.
TLDR
Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was found to have an IC50 of 140nM for PAR-4 with 71-fold selectivity versus PAR-1 (PAR-1IC50=10μM). Expand
Selective Activation of M4 Muscarinic Acetylcholine Receptors Reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents
TLDR
VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. Expand
Benzodiazepines as potent and selective bradykinin B1 antagonists.
TLDR
In vivo efficacy, comparable to morphine, was demonstrated for lead compounds in a rodent hyperalgesia model and novel benzodiazepines were designed that display subnanomolar affinity for the bradykinin B(1) receptor. Expand
Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe.
TLDR
This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M(1) PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN, which afforded VU0405652 (ML169), a potent, selective and brain penetrant M-1 PAM with an in vitro profile comparable to the prototypical M( 1) Pam, BQCA, but with an improved brain to plasma ratio. Expand
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