Nondepolarizing relaxants: new concepts and new drugs

Synthesis of Ultra-Short-Acting Neuromuscular Blocker GW 0430: A Remarkably Stereo- and Regioselective Synthesis of Mixed Tetrahydroisoquinolinium Chlorofumarates

“…Neuromuscular blockers (NMBs) are widely used in anesthesia to provide skeletal muscle relaxation during surgery and facilitate intubation of the trachea. Nondepolarizing NMBs are a highly desirable class due to their excellent clinical and safety profiles . NMBs possessing an ultra-short duration of action are required in emergency, routine surgical, and postoperative settings .…”

Bis- and Mixed-Tetrahydroisoquinolinium Chlorofumarates: New Ultra-Short-Acting Nondepolarizing Neuromuscular Blockers

“…Nondepolarizing NMBs are nicotinic acetylcholine receptor antagonists and are devoid of the side effects typically associated with depolarizing relaxants. A number of short, intermediate, and long-acting nondepolarizing NMBs are available in the clinic; however, no ultra-short-acting nondepolarizing NMB is currently available to anesthesiologists who have long recognized the need for a nondepolarizing succinylcholine replacement. , …”

“…Chemodegradation of drug substance in vivo could provide a clinical advantage by eliminating the problems associated with prolonged neuromuscular blockade in patients with low plasma cholinesterase activity . The chlorofumarates listed in Table are significant additions to the NMB family as they combine good potency (ED 95 < 0.2 mg/kg), rapid onset, and ultra-short durationthree qualities not typically associated with a single nondepolarizing relaxant …”

“…A number of short, intermediate, and long-acting nondepolarizing NMBs are available in the clinic; however, no ultra-short-acting nondepolarizing NMB is currently available to anesthesiologists who have long recognized the need for a nondepolarizing succinylcholine replacement. 3,4 We recently launched a medicinal chemistry program to discover 5 an ultra-short-acting nondepolarizing NMB, and in the course of this work we synthesized the bisand mixed-tetrahydroisoquinolinium fumarates 1-6. The structures and absolute stereochemistries of these new NMBs are provided in Chart 1.…”

“…20 The chlorofumarates listed in Table 2 are significant additions to the NMB family as they combine good potency (ED 95 < 0.2 mg/kg), rapid onset, and ultrashort durationsthree qualities not typically associated with a single nondepolarizing relaxant. 4 The NMB properties of 6a recently led to its clinical evaluation as an ultra-short-acting nondepolarizing succinylcholine replacement. A full account of the chemistry and structure-activity relationships leading to the discovery of this potentially useful adjunct to surgical anesthesia will be reported in due course.…”