A
Serc
Class of Lltralong-Acting Local Anesthetics
It ha- long tieeii recogiiizecl that idrenergic blocltiiig :igeiit- of the haloeth!.lnniiiie-ts pe block thohe actioiih of iiorepinephriiie mediated by the a receptor by ;i (1) cyclizatioii to torm an :iziriniatiuii of :I reverqible complex between the aairidiiiiuni ioii a i i t l :iii niiioriic -ite on thtb receptor. atid ( 3 ) renctioii of the :iziridiiiium ion with i t nucleophilic group 011 the receptor to foi m a covuleiit el, 111:i) hth lTJ)re-C~lltCYl b!. the folio\\ iiig e.clu:itioii.
--+A-
\
.A
&
T h e activity of :i giveii agent ~ ~ i depend ll upoii it. abilit). to penetrate to a biopha-e : i d to form the required uziridinium ioiis a+ well a- iipoii its afinit>, for t h e receptor. The qpecificity for the a-adrenergic receptor hhould clepeiid upon the ability of I1 aiid I
4
R
Analyses
C, H, Br, Y C, H, Br, N Bra
The 2-(3-amino-2,4,6-triiodophenyl)alkanoicacids (Table T'I) and their acyl derivatives (Table T'II) showed predominantly urinary excretion; S-alkylation (Table T7111) enhanced biliary excretion. For comparison iopanoic acid was tested under the same conditions giving LDSo p.0. = 15-10 mg/kg and LDio i.v. = 2% m g k g (mouse), biliary excretion 28%, urinary excretion 13% (rabbit). For further investigation 200 mg/kg of compounds 37,38, and 40 in suspension in 5% arabic gum solution were administered orally to dogs. Opacification of the gallbladder and of bile (3) J. T. Litchfield and F. Wileoxon, J . Pharmncol. E x p . Ther., 96, 99 (1949). (4) E B. Sandell and J. h l . Iiolthoff, J. dmer Ciiem. Soc., 56, 1426 (1939). ( 5 ) Technikon Instruments Corporation "N" Method File 5 - 5 6
