PHARMACOLOGICAL IN-VITRO CHARACTERIZATION OF THE ARECOLINE BIOISOSTERE, LU 25-109-T, A MUSCARINIC COMPOUND WITH M-1-AGONISTIC AND M-2 M-3-ANTAGONISTIC PROPERTIES/

The arecoline bioisostere, Lu 25-109-T, displays a pharmacological pro file of a partial muscarinic agonist with a several-fold higher affini ty for cortical M-1 receptors than for brain stem M-2 receptors and sa livary glands M-2 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 (M-1/M-2/M-3), at the rat superior cervical ganglion (M-1) and at cells transfected with cloned human mi muscarinic recept ors and as an antagonist at guinea pig left atrium (M-2) and cultured cerebellar granule cells (M-3) Lu 25-109-T readily passes the blood-br ain barrier in mice and has a bioavailability of 42% at oral administr ation although with a short half-life (t(1/2) = 41 min). The results i ndicate that Lu 25-109-T is acting selectively on muscarinic receptors . In functional in vitro assays Lu 25-109-T acts as an M-1 (and m1) pa rtial agonist and at the same time as an M-2 and M-3 antagonist. (C) 1 997 Wiley-Liss, Inc.