The Importance of Stereoisomerism in Muscarinic Activity

Beckett, A. H.; Harper, N. J.; Clitherow, J. W.

doi:10.1111/j.2042-7158.1963.tb12799.x

Cited by 59 publications

(25 citation statements)

References 22 publications

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“…Because of sustained contraction of the ileum, presumably caused by accumulated endogenous ACh, , 1963;Cocolas & Robinson, 1970). Furthermore, in contrast to untreated ileum, the three compounds investigated produced the same maximum response in DFP-PrBCM-treated tissue ( Table 2).…”

Section: Resultsmentioning

confidence: 84%

Dissociation constants and relative efficacies of acetylcholine, (+)‐ and (‐)‐methacholine at muscarinic receptors in the guinea‐pig ileum

Ringdahl

1986

British J Pharmacology

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Dissociation constants (KA) and relative efficacies of acetylcholine, (+)‐methacholine and (‐)‐methacholine at muscarinic receptors in the guinea‐pig isolated ileum were determined in the absence and presence of the cholinesterase inhibitor diisopropylfluorophosphate. The method used involved analysis of dose‐response data before and after fractional inactivation of receptors with propylbenzilylcholine mustard. The KA values, estimated after cholinesterase inhibition, of acetylcholine, (+)‐ and (‐)‐methacholine were 1.7, 2.0 and 620 μM, respectively. The large (730 fold) difference in spasmogenic activity between (+)‐ and (‐)‐methacholine is due primarily to a difference in affinity for ileal muscarinic receptors although differences in efficacy (2 to 4 fold) also contribute. It is suggested that the methyl group at the chiral centre of (+)‐methacholine has no apparent effect on the binding to muscarinic receptors, whereas the corresponding methyl group of (‐)‐methacholine interferes with binding, presumably by stabilizing a conformation of the drug which does not fit the receptor very well.

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Section: Resultsmentioning

confidence: 84%

Dissociation constants and relative efficacies of acetylcholine, (+)‐ and (‐)‐methacholine at muscarinic receptors in the guinea‐pig ileum

Ringdahl

1986

British J Pharmacology

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“…On the other hand, a well-defined difference between acetylcholine derivatives and alkyl acetates in their interactions with acetylcholinesterase active surface has been found in the present work. In contrast to the interaction with acetyl p-methylcholine (I) [43] the enzyme did not exhibit stereoselectivity in the case of see-butyl acetate (11) which has an asymmetric centre similar to that of compound (I). The enzymic hydrolysis of sec-butyl acetate under the…”

Section: Discussionmentioning

confidence: 93%

Structure‐Activity Relationships in Acetylcholinesterase Reactions

Järv¹,

Kesvatera²,

Aaviksaar³

1976

European Journal of Biochemistry

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The Michaelis-Menten parameters k,,,, Ks(app) and the second-order rate constants kll = kz/K, of acetylcholinesterase-catalyzed hydrolysis of 25 acetic esters with non-ionic leaving groups have been determined at 25 "C and pH 7.5 in 0.1 5 M KCI. A linear relationship between the substrate noncovalent binding capacity and the leaving group hydrophobicity, and a multiparameter correlation of the acetylation reaction rate constant logarithm with the leaving group inductive effect, hydrophobicity, and steric effect, have been established. The acetyl-enzyme deacetylation rate constant has been calculated. Taken together, a fairly complete understanding of acetylcholinesterase specificity is possible.The data are consistent with a model of the acetylcholinesterase active site, in which the catalytically active groups are located at the bottom of a jaws-like slit with a limited range of hydrophobic walls that provide the sorption of the substrate leaving groups not longer than that in n-butyl acetate.Acetylcholinesterase has been shown to hydrolyse, in addition to its specific substrate acetylcholine, many other acetic esters [l]. This provides a prospect for extensive study of the influence of substrate leaving group structure on the effectiveness of acetylcholinesterase-catalyzed hydrolysis. A conclusion that both the substituent inductive effect and hydrophobicity are important in acetylcholinesterase reactions, can be drawn from the results of previous studies [2-121. In this paper we are concerned with quantitative evaluation of these influences in the reaction series CH3C-(O)OX, where the group X includes hydrocarbon chains and various non-ionic electronegative substituents (see Table 1).Up to now the analysis of enzyme kinetics data by means of correlation equations has been carried out mainly on chymotrypsin-catalyzed reactions [13 -161. In accordance with the three-step reaction scheme(2) (3) the structure-activity relationship for the non-covalent binding step (3) has been given by the equation where K, = k-l/kl, while E is enzyme, S substrate, ES the enzyme-substrate complex, EA the acyl-enzyme, PI and P2 the first and second products. For the acylation reaction (2), as well as for the deacylation (3), the multiparameter correlation equation log k2 = log k2" + @* O* + van + 6 E, ( 5 ) can be applied. The parameters e*, q and 6 in the equations are the intensity factors of the inductive effect, hydrophobicity and steric effect, respectively. The constants cr* and E, have their usual meanings as in physical organic chemistry [17]. The hydrophobicity constants n have been introduced by Hansch [18,19].Under the conditions where the product and substrate inhibition phenomena could be left out of consideration, the reaction sequence (1 -3) would be applicable to the acetylcholinesterase-catalyzed hydrolysis of esters [20]. According to the reaction scheme the meaning of the constants kcat and Ks(app) (K, = K, if k2 < k-l) in the Michaelis-Menten equation depends on the values of the ratio kz/kj as follows : (7)

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“…The structure of this peripheral receptor has been discussed by Beckett, Harper, Clitherow & Lesser (1961), Beckett, Harper & Clitherow (1963), Waser (1961) and Belleau & Puraneft (1963) with particular reference to the activity of muscarine, muscarone and the highly active quaternary salts of 5-dimethylaminomethyl-2-methyl-1,3-dioxolane. Beckett et al (1963) have suggested that muscarinic drugs may interact with the receptor at an anionic site (site 1), and a cationic site (site 2), separated by 3 to 3.5 A, and also at a third site located at a distance of 5 to 7 A from the anionic site. Because of the existence of free rotation about the =C-CH2 bond oxoTremorine can exist in two planar forms, cisoid or transoid.…”

Section: Resultsmentioning

confidence: 99%