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Titolo:
Differential inhibition of [H-3]-oxotremorine-M and [H-3]-quinuclinidyl benzilate binding to muscarinic receptors in rat brain membranes with acetylcholinesterase inhibitors
Autore:
Lockhart, B; Closier, M; Howard, K; Steward, C; Lestage, P;
Indirizzi:
Inst Rech Servier, Div Cerebral Pathol, F-78290 Croissy Sur Seine, France Inst Rech Servier Croissy Sur Seine France F-78290 ssy Sur Seine, France
Titolo Testata:
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
fascicolo: 4, volume: 363, anno: 2001,
pagine: 429 - 438
SICI:
0028-1298(200104)363:4<429:DIO[A[>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
HIGH-AFFINITY BINDING; ALLOSTERIC ANTAGONISTS; H-3 ACETYLCHOLINE; ION CHANNEL; AGONIST; ANTICHOLINESTERASES; SUBTYPE; DRUGS; CELLS; ORGANOPHOSPHATES;
Keywords:
muscarinic; acetylcholinesterase; oxotremorine-M; fasciculin-2; acetylcholinesterase inhibitor; cholinergic;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
36
Recensione:
Indirizzi per estratti:
Indirizzo: Lockhart, B Inst Rech Servier, Div Cerebral Pathol, 125 Chemin Ronde, F-78290 Croissy Sur Seine, France Inst Rech Servier 125 Chemin Ronde Croissy Sur Seine France F-78290
Citazione:
B. Lockhart et al., "Differential inhibition of [H-3]-oxotremorine-M and [H-3]-quinuclinidyl benzilate binding to muscarinic receptors in rat brain membranes with acetylcholinesterase inhibitors", N-S ARCH PH, 363(4), 2001, pp. 429-438

Abstract

The potential interaction of acetylcholinesterase inhibitors with cholinergic receptors may play a significant role in the therapeutic and/or side-effects associated with this class of compound. In the present study, the capacity of acetylcholinesterase inhibitors to interact with muscarinic receptors was assessed by their ability to displace both [H-3]-oxotremorine-M and[H-3]-quinuclinidyl benzilate binding in rat brain membranes. The [H-3]-quinuclinidyl benzilate/[H-3] -oxotremorine-M affinity ratios permitted predictions to be made of either the antagonist or agonist properties of the different compounds. A series of compounds, representative of the principal classes of acetylcholinesterase inhibitors, displaced [H-3]-oxotremorine-M binding with high-to-moderate potency (ambenonium > neostigmine=pyridostigmine=tacrine > physostigimine > edrophonium=galanthamine > desoxypeganine) whereas only ambenonium and tacrine displaced [H-3]-quinuclinidyl benzilate binding. Inhibitors such as desoxypeganine, parathion and gramine demonstrated negligible inhibition of the binding of both radioligands. Scatchard plots constructed from the inhibition of [H-3]-oxotremorine-M binding in the absence and presence of different inhibitors showed an unaltered B-max and a reduced affinity constant, indicative of potential competitive or allosteric mechanisms. The capacity of acetylcholinesterase inhibitors, with the exception of tacrine and ambenonium, to displace bound [H-3]-oxotremorine-M inpreference to [H-3]-quinuclinidyl benzilate predicts that the former compounds could act as potential agonists at muscarinic receptors. Moreover, therank order for potency in inhibiting acetylcholinesterase (ambenonium > neostigmine=physostigmine=tacrine > pyridostigmine=edrophonium=galathamine > desoxypeganine > parathion > gramine) indicated that the most effective inhibitors of acetylcholinesterase also displaced [H-3]-oxotremorine-M to the greatest extent. The capacity of these inhibitors to displace [H-3]-oxotremorine-M binding preclude their utilisation for the prevention of acetylcholine catabolism in rat brain membranes, the latter being required to estimate the binding of acetylcholine to [H-3]-oxotremorine-M-labelled muscarinic receptors. However, fasciculin-2, a potent peptide inhibitor of acetylcholinesterase (IC50 24 nM), did prevent catabolism of acetylcholine in rat brain membranes with an atypical inhibition isotherm of [H-3]-oxotremorine-M binding, thus permitting an estimation of the "global affinity" of acetylcholine (K-i 85 nM) for [H-3] -oxotremorine-M-labelled muscarinic receptors in rat brain.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/09/20 alle ore 00:56:59