Structure-Affinity Relationships and Stereospecificity of Several Homologous Series of Local Anesthetics for the beta2-Adrenergic Receptor

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 (pK_i 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 (pK_i 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 (pK_i 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 beta_2-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)