title: 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.
authors.affiliation: GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. eric.e.boros@gsk.com
authors.forename: Eric E
authors.initials: EE
authors.lastname: Boros
authors.forename: Vicente
authors.initials: V
authors.lastname: Samano
authors.forename: John A
authors.initials: JA
authors.lastname: Ray
authors.forename: James B
authors.initials: JB
authors.lastname: Thompson
authors.forename: David K
authors.initials: DK
authors.lastname: Jung
authors.forename: Istvan
authors.initials: I
authors.lastname: Kaldor
authors.forename: Cecilia S
authors.initials: CS
authors.lastname: Koble
authors.forename: Michael T
authors.initials: MT
authors.lastname: Martin
authors.forename: Virgil L
authors.initials: VL
authors.lastname: Styles
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mook
authors.forename: Paul L
authors.initials: PL
authors.lastname: Feldman
authors.forename: John J
authors.initials: JJ
authors.lastname: Savarese
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Belmont
authors.forename: Eric C
authors.initials: EC
authors.lastname: Bigham
authors.forename: G Evan
authors.initials: GE
authors.lastname: Boswell
authors.forename: Mir A
authors.initials: MA
authors.lastname: Hashim
authors.forename: Sanjay S
authors.initials: SS
authors.lastname: Patel
authors.forename: James C
authors.initials: JC
authors.lastname: Wisowaty
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bowers
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Moseley
authors.forename: John S
authors.initials: JS
authors.lastname: Walsh
authors.forename: Mindy J
authors.initials: MJ
authors.lastname: Reese
authors.forename: Randy D
authors.initials: RD
authors.lastname: Rutkowske
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Sefler
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spitzer
mesh_terms: D000818:Animals; D000840:Anisoles / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D005650:Fumarates / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D009466:Neuromuscular Blocking Agents / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013386:Succinates / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C475432:2-chloro-4-(3-(6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-2-isoquinolinio)propyl)-1-(3-(2-methyl-6,7-dimethoxy-1-((3,4,5-trimethoxyphenyl)methyl)-1,2,3,4-teterahydro-2-isoquinolinio)propyl)-2-butenedioate; D000840:Anisoles; D005650:Fumarates; D007546:Isoquinolines; D009466:Neuromuscular Blocking Agents; D000644:Quaternary Ammonium Compounds; D013386:Succinates