A NEW 3,4-DIAMINOPYRIDINE DERIVATIVE ON NEUROMUSCULAR TRANSMISSION AND CENTRAL NERVOUS SYSTEM IN RATS

Abstract

S392 INTRODUCTION: LF-14, a derivative of 3,4-diaminopyridine (3,4-DAP), antagonizes the neuromuscular (NM) blocking effect of nondepolarizing muscle relaxants. It also has beneficial effects on disorders of cholinergic function, such as old age or Alzheimer's disease in rat model [1,2]. LF-14, however, has a very short shelf-life (1 week). We, therefore synthesized 3-maleimino-4-aminopyridine (LI-2), which is a very stable dervative of 3,4-DAP. LI-2 was investigated for its effects on NM transmission and convulsive effects on the central nervous system (CNS) in rats. METHODS: The experiments were carried out in accordance with NIH and Institutional Animal Care guidelines. In vitro studies were performed on the rat phrenic nerve-hemidiaphragm preparations, suspended in modified Krebs' solution [3] at 37[degree sign]C, aerated with 95% O2 -5% CO2. In in vivo experiments, Sprague-Dawley rats were anesthetized with i.p. pentobarbital and urethane, tracheostomized and ventilated with O2. Then the sciatic nerve-tibialis anterior muscle preparations were made. The phrenic and sciatic nerves were stimulated with supramaximal square wave impulses (0.2 ms, 0.1 Hz). A 90% steady state NM block was produced with d-tubocurarine (d-Tc), pancuronium, vecuronium and also Mg2+ (in vitro only). The ED50 and ED90 of LI-2 were determined from the cumulative log dose-response regression lines. In separate experiments, 2.0x ED90 dose of LI-2 were administered to evaluate antagonist and CNS effects. RESULTS: The potencies of LI-2 in vitro and in vivo NM studies are shown in Table 1. The duration of the antagonist effect of 2.0x ED90 of LI-2 was about 217 +/- 21 minutes (mean +/- SEM). 2.0x ED90 did not produce any convulsive effect during in vivo study. LI-2 also antagonized Mg2+ induced NM block.Table 1: Antagonism of d-Tc, pancuronium and vecuronium induced NM block by LI-2CONCLUSION: Since Mg2+ induced NM block is not reversed by cholinesterase inhibitors such as neostigmine, the mechanism of antagonist effect of LI-2 is similar to 3,4-DAP. LI-2 may, therefore, have clinical utility in reversing NM block at the end of surgery, and in treating diseases associated with cholinergic dysfunctions.