Impact of species variability and 'probe-dependence' on the detection and in vivo validation of allosteric modulation at the M4 muscarinic acetylcholine receptor.

ABSTRACT:

Background and purpose

We recently characterized LY2033298 as a novel allosteric modulator and agonist at M(4) muscarinic acetylcholine receptors (mAChRs). Evidence also suggested a difference in the potency of LY2033298 at rodent relative to human M(4) mAChRs. The current study investigated the basis for the species difference of this modulator and used this knowledge to rationalize its in vivo actions.

Experimental approach

LY2033298 was investigated in vitro in CHO cells stably expressing human or mouse M(4) mAChRs, using assays of agonist-induced ERK1/2 or GSK-3α phosphorylation, [(35) S]-GTPγS binding, or effects on equilibrium binding of [(3) H]-NMS and ACh. The in vivo actions of LY2033298 were investigated in a mouse model of amphetamine-induced locomotor activity. T

SUBMITTER: Suratman S 

PROVIDER: S-EPMC3057301 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature