Actions at neuromuscular and esteratic cholinoceptive sites of some phenylene diacryloyl bis-cholinium esters
Savarese, J.J.; Ginsburg, S.; Braswell, L.; Kitz, R.J.
Journal of Pharmacology and Experimental Therapeutics 208(3): 436-445
1979
ISSN/ISBN: 0022-3565 PMID: 430363 Document Number: 140934
Nineteen analogous bis-cholinium esters of m- and p-phenylene diacrylic acids were synthesized. Their actions at esteratic cholinoceptive sites and at the neuromuscular junction were defined. Inhibition of eel acetylcholinesterase (EC 3.1.1.7) and human plasma cholinesterase (EC 3.1.1.8) was studied in vitro by the pH-stat method. Human plasma cholinesterase-catalyzed hydrolysis rates of the new compounds were determined and compared with data for succinylcholine. Actions at the neuromuscular junction were defined in chloralose-anesthetized cats. Three basic mechanisms were evident in separate representative compounds of the series: depolarizing neuromuscular block, facilitation of neuromuscular transmission without indication of depolarization and nondepolarizing neuromuscular block. Most compounds bearing an unhindered ester linkage had a short duration of action (10 min or less) at dosage producing 95% neuromuscular blockade. The duration of block was prolonged by methyl substitution .beta. to the quaternary N atoms or by replacement of the ester by amide linkages. Neuromuscular blocking activity, whether depolarizing or nondepolarizing in nature, was greatest in structures bearing relatively hydrophilic N-substitutions, whereas facilitating or anticholinesterase activity predominated in compounds quaternized with planar aromatic hydrophobic groups. A chemically definable pharmacological continuum in diquaternary ester substances dependent on the nature of the quaternary substituents was suggested.