A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M receptor agonist HTL0018318 in patients with mild-to-moderate Alzheimer's disease.

Introduction: This study examined the safety and pharmacodynamic effects of selective muscarinic M receptor orthosteric agonist HTL0018318 in 60 patients with mild-to-moderate Alzheimer's disease (AD) on background donepezil 10 mg/day.

Methods: A randomized, double-blind, placebo-controlled 4-week safety study of HTL0018318 with up-titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition.

Results: Treatment-emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration.

Unifying family A GPCR theories of activation.

Several new pairs of active and inactive GPCR structures have recently been solved enabling detailed structural insight into the activation process, not only of rhodopsin but now also of the β2 adrenergic, M2 muscarinic and adenosine A2A receptors. Combined with structural analyses they have enabled us to examine the different recent theories proposed for GPCR activation and show that they are all indeed parts of the same process, and are intrinsically related through their effect on the central hydrophobic core of GPCRs. This new unifying general process of activation is consistent with the identification of known constitutively active mutants and an in-depth conservational analysis of significant residues implicated in the process.