STRUCTURE-AFFINITY RELATIONSHIPS AND STEREOSPECIFICITY OF SEVERAL HOMOLOGOUS SERIES OF LOCAL-ANESTHETICS FOR THE BETA(2)-ADRENERGIC RECEPTOR

Local anesthetics inhibit binding of ligands to beta(2)-adrenergic rec eptors (beta(2)ARs), and, as a consequence, inhibit intracellular cAMP production. We hypothesized that among homologous local anesthetics, their avidity at inhibiting binding of tritiated dihydroalprenolol(H-3 -DHA) to beta(2)ARs would increase with increas ing length of alkyl su bstituents and would demonstrate stereospecificity. Specific binding o f H-3-DHA to human beta(2)ARs was assayed in the presence of six diffe rent members of the 1-alkyl-2,6-pipecoloxylidide class of local anesth etics (including mepivacaine, ropivacaine, and bupivacaine), the R(+) and S(-)bupivacaine enantiomers, lidocaine, prilocaine, etidocaine, pr ocaine, and tetracaine. Avidity of binding to beta(2)ARs increased wit h 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 [ropivac aine], butyl [bupivacaine], pentyl, and octyl derivatives, respectivel y). We found no evidence for bupivacaine stereospecificity (pK(i) valu es = 4.3 and 4.9 for the S(-) and R(+) isomers, respectively). Other a mide and ester local anesthetics also showed increasing potency with i ncreasing 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 inhi bition of beta(2)AR binding and alkyl chain length resembles the corre lation between local anesthetic potency at nerve block and increased a lkyl chain length. The lack of clear stereospecificity is consistent w ith the relatively low potency these agents demonstrate at inhibition of beta(2)AR binding. Finally, the relatively potent inhibition of bet a(2)ARs by etidocaine, tetracaine, and bupivacaine suggests that their propensity for cardiovascular depression after accidental intravenous overdose could result from beta(2)AR or beta(2)AR blockade and inhibi tion of cAMP production Implications: Local anesthetics demonstrate a rank order of avidity for displacing ligands from beta(2)-adrenergic r eceptors such that larger molecules displace ligands at lower concentr ations than smaller local anesthetic molecules. This relationship betw een molecular size and receptor avidity could explain the greater prop ensity for cardiovascular toxicity of relatively large local anestheti cs such as bupivacaine.