Neuromuscular Blocking Activity and Therapeutic Potential of Mixed-Tetrahydroisoquinolinium Halofumarates and Halosuccinates in Rhesus Monkeys

Abstract

Structure-activity relationships in rhesus monkeys for a novel mixed-onium class of ultra-short-acting nondepolarizing tetrahydroisoquinolinium neuromuscular blockers (NMBs) are described. Bis-onium chlorofumarate 20a with (1R,2S)-benzyltetrahydroisoquinolinium groups was a potent lead compound (ED(95) = 0.079 mg/kg) with an ultra-short duration of NMB effect (7.1 min) and a selectivity index (SI: defined as a ratio of the cardiovascular threshold dose to the ED(95)) similar to that of mivacurium (3). The mean threshold dose for cardiovascular effects with 20a was ca. 20 times its ED(95) value (SI = 20). A novel mixed-onium analogue of 20a was prepared by replacing the benzyltetrahydroisoquinolinium group distal to the fumarate chlorine atom with a (1S,2R)-phenyltetrahydroisoquinolinium moiety. The resulting mixed-onium chlorofumarate 24a displayed good NMB potency (ED(95) = 0.063 mg/kg), ultra-short duration of action (5.6 min) and an improved selectivity index (SI = 57). Several other mixed-onium derivatives containing octanedioate (25a; ED(95) = 0.103 mg/kg), difluorosuccinate (27c; ED(95) = 0.056 mg/kg), and fluorofumarate (28a; ED(95) = 0.137 mg/kg) linkers were also potent, ultra-short-acting NMBs with good to excellent selectivity index values (SI = 37-96). Octanedioate 25a was longer acting at higher doses compared to difluorosuccinate 27c and chlorofumarate 24a. Durations of NMB effect following a 0.4 mg/kg bolus dose (100% block) of 25a, 27c, and 24a were 16.9, 13.0, and 10.0 min, respectively. Recovery time for mixed-onium chlorofumarate 24a following a 1 h continuous infusion at 10-20 microg/kg/min (95-100% block) was ca. 5 min which is similar to that observed following a 0.2 mg/kg bolus dose of this compound and indicates a lack of cummulative effects. Preliminary studies with chlorofumarate 24a in whole human blood revealed that mixed-onium thiazolidine 29 was the major metabolite and that plasma cholinesterases do not play the primary role in duration of NMB effect. The NMB properties of 24a in rhesus monkeys led to its clinical evaluation as a possible alternative to succinylcholine.

Novel neuromuscular blocking drugs and antagonists

“…1) [12]. Subsequent invitro investigation revealed this interaction to be relatively fast (reaction half-time of $15 s) and to yield an adduction product with very little affinity for nicotinic receptors at the motor end plate [13,14].…”

“…Although seminal work related to gantacurium and related compounds was accomplished in the early 1990s, it was not until 1996 that gantacurium (initially GW280430) was identified and subsequently synthesized [9][10][11][12]. In contrast to the symmetric structure of many enantiomericbisquaternary compounds that have been studied, gantacurium is an asymmetric bis-onium ester of a-chlorofumaric acid (Fig.…”

Update on neuromuscular pharmacology

“…Gantacurium represents a new class of nondepolarizing neuromuscular blockers called asymmetric mixed-onium chlorofumarates [29]; it is degraded by two chemical mechanisms, neither of which is enzymatic: (1) rapid formation of an apparently inactive cysteine adduction product; and (2) slower hydrolysis of the ester bond adjacent to the chlorine substitution to presumably inactive hydrolysis products [29]. Exogenous administration of cysteine/ glutathione can accelerate the antagonism of gantacurium-induced neuromuscular blockade.…”

Recent Advances in Neuromuscular Blocking Agents

“…In search for the substitution of the ultra-short-acting NMB suxamethonium 5, scientists at GlaxoSmithKline examined a new class of non-depolarizing, mivacuriumderived NMBs possessing a chlorofumarate moiety in the middle-chain spacer [42]. Unlike mivacurium 14, which is a mixture of three diastereomers, all compounds were synthesized as single stereoisomers.…”

“…The major deactivation pathway of 18a involves the reaction with serum cysteine to give the inactive thiazolidine 26 (Fig. 5) [42]. Table 2).…”