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Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2003 Jun 05; Vol. 46 (12), pp. 2502-15. - Publication Year :
- 2003
-
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.
- Subjects :
- Animals
Anisoles blood
Anisoles pharmacology
Blood Pressure drug effects
Fumarates blood
Fumarates pharmacology
Heart Rate drug effects
Humans
In Vitro Techniques
Isoquinolines blood
Isoquinolines chemistry
Isoquinolines pharmacology
Macaca mulatta
Male
Muscle Contraction drug effects
Muscle, Skeletal drug effects
Muscle, Skeletal physiology
Neuromuscular Blocking Agents blood
Neuromuscular Blocking Agents pharmacology
Quaternary Ammonium Compounds chemistry
Quaternary Ammonium Compounds pharmacology
Stereoisomerism
Structure-Activity Relationship
Succinates blood
Succinates pharmacology
Anisoles chemical synthesis
Fumarates chemical synthesis
Isoquinolines chemical synthesis
Neuromuscular Blocking Agents chemical synthesis
Quaternary Ammonium Compounds chemical synthesis
Succinates chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 46
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12773054
- Full Text :
- https://doi.org/10.1021/jm020574+