PCS1055

This is a reasonably selective, and potent (6nM) M4 antagonist - selectivity for M4 is difficult to achieve, so this in itself makes this worth considering. It is well characterised pharmacologically and is a neutral competitive antagonist at the M4 receptor. It shows 30 fold selectivity vs M2, and better against the other muscarinic receptors. However, there are two reasons I cannot unambiguously recommend it as an in vitro probe - one is the acetylcholinesterase activity (20 fold selective, 120nM), and the second is the complete lack of broader selectivity information. The paper somewhat unhelpfully states: "Further bio-activity profiling studies conducted during our studies with PCS1055 did not note any significant potency or activity across a panel of other targets (data not shown)." I have rated this 3* - but it's just scraped in to that level for me, and I would advise using it as a secondary probe alongside another compound - see below. In vivo the compound shows reasonable exposure; however its brain exposure at the reported 30mpk ip dose is too low to be useful as described in the paper, probably due to efflux (brain:plasma unbound ratio is <<1). In the absence of other probes, my recommendation would be use this compound alongside one of the probes in this publication from Vanderbilt- https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00363 - the lead compound is potent and more selective vs M2, but does have a liability against sigma-1.