title: Functional characterization of muscarinic autoreceptors in rat and human neocortex.
abstract: Electrically evoked overflow of [(3)H]acetylcholine in slices of rat neocortex and of human neocortex (freshly obtained during neurosurgical treatment of epilepsy or deep-seated tumors) was used to functionally characterize the muscarinic receptor subtype, which mediates autoinhibition of acetylcholine release in these tissues. In the rat neocortex, the following pK(B) values [CI(95)] were calculated from the shifts to the right of the concentration-response curves of the full agonist oxotremorine in presence of subtype preferring muscarinic receptor antagonists: tripitramine: 9.1 [8.8, 9.4], tripinamide: 8.6 [8.5, 8.7], AQ-RA 741 (11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido(2,3-b)[1,4]benzodiazepine-6-one): 8.2 [8.0, 8.4], himbacine: 8.0 [7.9, 8.1], 4-diphenylacetoxy-N-methylpiperidine methobromide: 8.0 [7.8, 8.1], methoctramine: 7.5 [7.4, 7.6], AF-DX 116 (11[[2-[(diethyl-amino)methyl]-1-piperidinyl] acetyl] 5,11-dihydro-6H-pyrido(2,3-b)[1,4]benzodiazepine-6-one): 7.1 [7.0, 7.3], hexahydro-sila-difenidol: 6.8 [6.7, 6.9], pirenzepine: 6.6 [6.4, 6.7], and 3,6a,11,14-tetrahydro-9-methoxy-2-methyl-12H-isoquino[1,2-b]pyrrolo[3,2-f] [1,3]benzoxazine-1-carboxylic acid ethyl ester (PD 102807): 6.0 [5.8, 6.2]. In the human neocortex the following values were found: tripitramine: 9.4 [9.3, 9.6], tripinamide: 9.0 [8.9, 9.2], AF-DX 116: 6.7 [6.4, 6.9], hexahydro-sila-difenidol: 6.6 [6.2, 6.9], and PD 102807: 6.5 [6.3, 6.6]. In correlation plots, these pK(B) values correspond best to published binding data on native or recombinant M(2) receptors but not to those on M(1), M(3), M(4), and M(5) receptors, suggesting that muscarinic autoreceptors of both the rat and human neocortex belong to the M(2) subtype. This observation lends further support to the development of M(2) receptor selective brain penetrating antagonists for application in Alzheimer's disease.
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Freiburg, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Stoll
authors.forename: Manfrid
authors.initials: M
authors.lastname: Eltze
authors.forename: Günter
authors.initials: G
authors.lastname: Lambrecht
authors.forename: Josef
authors.initials: J
authors.lastname: Zentner
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Feuerstein
authors.forename: Rolf
authors.initials: R
authors.lastname: Jackisch
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors / Q000145:classification / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000494:pharmacology; D019579:Neocortex / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000145:classification / Q000502:physiology*; D013045:Species Specificity
chemical_list: D017660:Autoreceptors; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic