PD 102807, a novel muscarinic M-4 receptor antagonist, discriminates between striatal and cortical muscarinic receptors coupled to cyclic AMP

In membranes of Chinese hamster ovary cells expressing the cloned human M-1 -M-4 muscarinic receptor subtypes, PD 102807, a novel M-4 selective antagon ist, was found to counteract the Mg receptor-induced stimulation of [S-35]- GTP gamma S binding to membrane G proteins with a pK(B) of 7.40, a value wh ich was 63-, 33- and 10-fold higher than those displayed at M-1 (pK(B) = 5. 60), M-2 (pK(B) = 5.88) and M-3 (pK(B) = 6.39) receptor subtypes, respectiv ely. In rat striatal membranes, PD 102807 antagonized the muscarinic inhibi tion of dopamine (DA) D-1 receptor-stimulated adenylyl cyclase with a pK(B) value of 7.36. In contrast, in membranes of rat frontal cortex, PD 102807 displayed lower potencies in antagonizing either the muscarinic facilitatio n of corticotropin releasing hormone (CRH)-stimulated adenylyl cyclase (pK( B) = 5.79) or inhibition of Ca2+/calmodulin (Ca2+/CaM)stimulated enzyme act ivity (pK(B) = 5.95). In each response investigated, PD 102807 interacted w ith muscarinic receptors in a manner typical of a simple competitive antago nist. These data provide additional evidence that PD 102807 is a M-4-recept or preferring antagonist and that this compound can discriminate the striat al muscarinic receptors inhibiting DA D-1 receptor activity from the cortic al receptors mediating the potentiation of CRH receptor signalling and the inhibition of Ca2+/CaM-stimulated adenylyl cyclase activity.