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• W4254336100 abstract "Local anesthetics inhibit binding of ligands to beta2-adrenergic receptors (beta2 ARs), and, as a consequence, inhibit intracellular cAMP production. We hypothesized that among homologous local anesthetics, their avidity at inhibiting binding of tritiated dihydroalprenolol (3) H-DHA) to beta2 ARs would increase with increasing length of alkyl substituents and would demonstrate stereospecificity. Specific binding of3 H-DHA to human beta2 ARs was assayed in the presence of six different members of the 1-alkyl-2,6-pipecoloxylidide class of local anesthetics (including mepivacaine, ropivacaine, and bupivacaine), the R(+) and S(-) bupivacaine enantiomers, lidocaine, prilocaine, etidocaine, procaine, and tetracaine. Avidity of binding to beta2 ARs increased with increasing length of the alkyl chain (pKi values = 2.4, 3.6, 4.3, 4.1, 4.1, 5.9 for the methyl [mepivacaine], ethyl, S(-)propyl [ropivacaine], butyl [bupivacaine], pentyl, and octyl derivatives, respectively). We found no evidence for bupivacaine stereospecificity (pKi values = 4.3 and 4.9 for the S(-) and R(+) isomers, respectively). Other amide and ester local anesthetics also showed increasing potency with increasing length of alkyl substituents (pKi values = 3.6, 3.8, and 4.3 for lidocaine, prilocaine, and etidocaine; 4.2 and 5.6 for procaine and tetracaine, respectively). The correlation between increased inhibition of beta2 AR binding and alkyl chain length resembles the correlation between local anesthetic potency at nerve block and increased alkyl chain length. The lack of clear stereospecificity is consistent with the relatively low potency these agents demonstrate at inhibition of beta2 AR binding. Finally, the relatively potent inhibition of beta2 ARs by etidocaine, tetracaine, and bupivacaine suggests that their propensity for cardiovascular depression after accidental intravenous overdose could result from beta2 AR or beta1 AR blockade and inhibition of cAMP production. Implications: Local anesthetics demonstrate a rank order of avidity for displacing ligands from beta2-adrenergic receptors such that larger molecules displace ligands at lower concentrations than smaller local anesthetic molecules. This relationship between molecular size and receptor avidity could explain the greater propensity for cardiovascular toxicity of relatively large local anesthetics such as bupivacaine. (Anesth Analg 1997;85:336-42)" @default.
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• W4254336100 date "1997-08-01" @default.
• W4254336100 modified "2023-09-25" @default.
• W4254336100 title "Structure-Affinity Relationships and Stereospecificity of Several Homologous Series of Local Anesthetics for the beta2-Adrenergic Receptor" @default.
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• W4254336100 doi "https://doi.org/10.1213/00000539-199708000-00017" @default.
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