Pharmacological in vitro characterization of the arecoline bioisostere, Lu 25-109-T, a muscarinic compound with M1-agonistic and M2/M3-antagonistic properties

Abstract

The arecoline bioisostere, Lu 25-109-T, displays a pharmacological profile of a partial muscarinic agonist with a several-fold higher affinity for cortical M1 receptors than for brain stem M2 receptors and salivary glands M3 receptors. The compound is selective for muscarinic receptors as it shows no or only low affinity for other receptor types. In functional assays Lu 25-109-T behaves as a partial agonist at the guinea pig ileum (M1/M2/M3), at the rat superior cervical ganglion (M1 and at cells transfected with cloned human ml muscarinic receptors and as an antagonist at guinea pig left atrium (M2) and cultured cerebellar granule cells (M3). Lu 25-109-T readily passes the blood-brain barrier in mice and has a bioavailability of 42% at oral administration although with a short half-life (t½=41 min). The results indicate that Lu 25-109-T is acting selectively on muscarinic receptors. In functional in vitro assays Lu 25-109-T acts as an M1 (and m1) partial agonist and at the same time as an M2 and M3 antagonist. Drug Dev. Res. 40:1–16, 1997. © 1997 Wiley-Liss, Inc.