[Curare-Like Camphor Derivatives and Their Biological Activity].

The synthesis and evaluation of muscle relaxant activity of series of dimeric camphor derivatives are described. Compounds in which the quaternary nitrogen atoms are separated by aromatic chain exhibited the highest efficiency as muscle relaxant. It was shown the screening of a charged atom and counter-ion does not have a significant role on the activity of the studied agents.

Recent advances in neuromuscular blocking agents.

Since the introduction of (+)-tubocurarine into anaesthetic and surgical practice (1942), a number of non-depolarizing neuromuscular blocking agents (NMBs) with improved pharmacological properties have been developed during the last sixty years. However, after withdrawal of rapacuronium from clinical use, there is still a need for an ultra-short acting non-depolarizing muscle relaxant with rapid onset as substitution for the polarizing suxamethonium, which has several undesirable side-effects. In this paper, structure-activity relationships within four different series of NMBs (tetrahydroisoquinolinium, bistropinyl diester, aminosteroid, and amino peptide analogues) published in this millennium have been reviewed. The NMB properties of the most promising drug candidates from each series were discussed and compared to those of the already existing muscle relaxants.

Synthesis of ganglioside epitopes for oligosaccharide specific immunoadsorption therapy of Guillian-Barré syndrome.

Guillain-Barré syndrome is a postinfectious, autoimmune neuropathy resulting in neuromuscular paralysis. Auto-antibodies, often induced by bacterial infection, bind to human gangliosides possessing monosialoside and diasialoside epitopes and impair the function of nerve junctions, where these ganglioside structures are highly enriched. Truncated gangliosides representive of GD3, GQ1b and GM2 epitopes have been synthesized as methyl glycosides and as a glycosides of an eleven carbon tether. The synthetic oligosaccharide ligands are structural mimics of these highly complex ganglioside epitopes and via their ability to neutralize or remove auto-antibodies have the potential for therapy, either as soluble blocking ligands administered systemically, or as immuno-affinity ligands for use as extracorporeal immunoadsorbents.

Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships.

A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.

Stereocontrolled synthesis of cis-dibenzoquinolizine chlorofumarates: curare-like agents of ultrashort duration.

The quaternizations of dibenzoquinolizines 9 and 14 with 3-halo-1-propanols are highly cis-selective (94-100% cis), results consistent with the N-methylation of O-methylcapaurine (7b), but in contrast to the proposed trans-stereochemistry of dibenzo[a,h]quinolizine methiodide 10 and the analogous quaternizations of 1-benzyl- and 1-phenylisoquinoline congeners 5b and 5c. In this report, we describe stereoselective preparation of the unique cis-dibenzoquinolizinium propanols 15 and 16and their transformation into bis- and mixed-onium chlorofumarates 19, 20ab, and 26. Dibenzo[a,g]quinolizinium propanol 15 was prepared enantioselectively in three steps from dihydroisoquinoline 11. Asymmetric transfer hydrogenation of 11 in the presence of triethylamine/formic acid and Noyori's chiral ruthenium catalyst 12 produced R-(-)-5',8-dimethoxynorlaudanosine (13) in 98% yield and 87% ee. Pictet-Spengler cyclization of 13 in formalin/formic acid afforded the dibenzo[a,g]quinolizine 14 in 65% yield. Quaternization of 14 with 3-chloro-1-propanol under Finkelstein conditions generated cis-dibenzoquinolizinium propanol 15 in 85% yield with >94% cis-selectivity. The cis-dibenzo[a,h]quinolizinium propanol 16 was obtained as a single stereoisomer by reaction of the known tetramethoxyquinolizine 9 with neat 3-iodo-1-propanol. Bis-onium chlorofumarates 18 and 19 and the mixed-onium derivative 20ab were prepared by a pool synthesis procedure from (1R)-trans-6a, 16, and chlorofumaryl chloride (17). Mixed-onium alpha-chlorofumarate 26 was synthesized from (1S)-trans-6d, 15 and (+/-)-trans-2,3-dichlorosuccinic anhydride (22), employing a recently disclosed chlorofumarate mixed-diester synthesis. The title compounds (19, 20ab, and 26) displayed curare-like effects of ultrashort duration in rhesus monkeys.

Non-depolarizing neuromuscular blocking activity of bisquaternary amino di- and tripeptide derivatives.

Herein we describe the synthesis of novel di- and tripeptide derivatives with two quaternary nitrogen groups attached and the biological testing of these compounds for neuromuscular blocking (NMB) activity in vitro and in vivo. The short peptide scaffold was selected because it offers potential for desired distance between the two pharmacophoric quaternary nitrogen groups, short duration of action, straightforward synthesis, and compatibility with an injectable formulation. From a small series of compounds 20c,e are identified as effective non-depolarizing NMB agents in vitro and in vivo in anesthetized cats and Rhesus monkeys with potencies similar to those of the clinical reference compounds rocuronium (4) and suxamethonium (2) (monkey ED(90) = 0.68, 0.23, 0.16, 5.04 micromol/kg, respectively). These new peptide derivatives 20c,e have similar potency and onset time but longer duration and slower recovery than the clinically used reference compounds. The structure-activity relationships described for this chemical series lead to the conclusion that the di- or tripeptide fragment can be regarded as an alternative template to the steroid or aliphatic ester of previously reported NMBs and within this tripeptide-derived series clog P correlates well with in vitro NMB activity.

[Synthesis and pharmacologic study of 1,5-dialkyl-1,5-benzodiazepine-2,4-dithiones]. / Synthèse et étude pharmacologique des 1,5-dialkyl-1,5-benzodiazépine-2,4-dithiones.

The synthesis and psychotropic activity of 1,5-diakyl-1,5-benzodiazepine-2,4-dithiones (alkyl = methyl, ethyl and benzyl radicals) were studied. Alkylation reactions were performed in catalytic conditions by phase transfer. These reactions allowed us to isolate only one kind of product N-alkyl. Acute toxicity studies were conducted according to European protocols in two species of appropriate mammals in order to discover the lethal doses. The activity of the compounds on the CNS was then studied, using a battery of compartmental tests used in psychopharmacology. No toxicity was demonstrated at therapeutic doses. Each product had a sedative effect more or less pronounced and different from the reference substance clobazam (Urbanyl). They also had myorelaxant and anxiolytic effects, even lengthening the hypnotic effect of thiopental (synergic action).

Stereochemical preferences for curarimimetic neuromuscular junction blockade IV: Monoquaternary ammonium probes possessing carbon and nitrogen asymmetry.

Two enantiomeric pairs of neuromuscular junction blocking agents were prepared in which an asymmetric carbon atom is adjacent to an asymmetric quaternized nitrogen moiety. The blocking agents were obtained from the enantiomers of laudanosine by stereoselective quaternization with benzyl and ethyl iodides. Curarimimetic potencies were measured with an in vivo cat hypoglossal nerve-tongue muscle preparation. The studies suggest that the asymmetry present in these structures does not lead to significant differences in blocking potency between enantiomers.

[Tricyclic homologs of piperazine. III. Synthesis of 4-substituted hexahydro-1H-2,6-methanopyrrolo[1,2a]pyrazines]. / Omologhi triciclici della piperazina. Nota III (1)--Sintesi di esaidro-1H-2,6-metanopirrolo[1,2-a]pirazine 4-sostituite.

The Authors describe the synthesis of some quaternary salts of the hexahydro-1H-2,6-methanopyrrolo[1,2-a]pyrazines mono or disubstituted at carbon-4. These were obtained directly by cyclization of the corresponding diazabicyclooctanes, by formation of a substituted ethylenic bridge between the two nitrogen atoms. The compounds were pharmacologically screened; the hypothesis of enhancement of curare-like activity in comparison with the unsubstituted derivatives was not confirmed.

Synthesis of a bifunctional coordination complex of osmium with curariform activity.

Based on the known curariform action of tris(bipyridyl)iron(II) sulfate and other complex ions, two series of bifunctional ligands designed to hold transition metal ions at approximately the same distance apart as the interquaternary ammonium distance in the potent neuromuscular block agents were synthesized. In the first series two 1,10-phenanthrolines (R1) were joined at the 2 position to form four compounds: R1CO-c-N(CH2CH2)2N-COR1, R1CONH-1,2-C6H10-NHCOR1, R1CONH-1,2-C6H4-NHCOR1, and R1CON(CH3)(CH2)2N(CH3)COR1. In the second series two terpyridines (R1) were joined by different chains to give R2(CH2)2CH=CH(CH2)2R2, R2CH2C(CH3)(OH)(CH2)2C(CH23)(OH)CH2R2, R2CH2C(CH3)(OH)C(CH3)(OH)CH2R2, and R2CH2(OH)-1,4-C6H10-(OH)CH2R2. Three other ligands in which the terpyridines were joined by 5-, 60, and 7-methylene groups were also made. The ligands were converted to nickel(II) complexes and the coordination of each nickel ion was completed by adding terpyridine. These were assayed by the intravenous mouse LD50 method. The most potent ligand, the di-hydroxy compound R2CH2(OH)-1,4-C6H10-(OH)CH2R2 was then converted to the bis(pyridinebipyridine)diosmium-(II) coordinated complex and assayed by the iv mouse LD50 method and by the ED50 isolated guinea-pig diaphragm method. By the iv mouse LD50 method, it was about twice as potent as d-tubocurarine and by the isolated diaphragm method, it was 16 times more potent. The compound has been called dihydroxyosmarine tetrachloride or DHO for short. The term "transarine" ions is proposed for transition metal coordination complexes having curariform action. The position of the transarine ions is discussed in the classification of cholinergic ligands, in structure-action relationships, and in relation to some current ideas on receptor mechanisms.

Stereochemical preferences for curarimimetic neuromuscular junction blockade I: enantiomeric monoquaternary amines as probes.

Seven pairs of monoquaternary enantiomeric neuromuscular junction blocking agents were prepared in which the carbon asymmetry is adjacent to the quaternized nitrogen moiety. The tertiary amines from which the blocking species were obtained are carnegine, laudanosine, N-methylpavine, corydine, isocorydine, glaucine, and boldine. Curarimimetic potencies, obtained with an in vivo cat tongue-hypoglossal nerve preparation, were obtained for the enantiomeric methiodides of each of these amines. Possible contributions to activity be preferential binding to blood components or by selective inhibition of acetylcholinesterase also were studied. The combined studies indicate that there is a modest preference by the neuromuscular junction of the cat for monoquaternary blockers with the (s)-confirguation.

Sterochemical preferences for curarimimetic neuromuscular junction blockade III: enantiomeric bisquaternary amines related to benzoquinonium as probes.

Enantiomeric neuromuscular junction blocking agents, which are of the benzoquinonium type but which have a methyl group introduced adjacent to the quaternary moieties to provide an asymmetric center were synthesized and tested to determine whether the neuromuscular junction exhibits the relatively modest (R) greater than (S) superiority shown toward previously tested bisquaternaries. Testing included a mouse inclined screen assay and an in vivo cat hypoglossal nerve-tongue preparation, as well as standard estimations of anticholinesterase activity since the candidate compounds are known to have such a component in their activity spectrum. The observed 2:1 difference in blocking activity favoring the compound with an (R)-configuration is the same as that for previously tested bisquaternaries, both in direction and magnitude. Furthermore, it cannot be accounted for by preferential inhibition of acetylcholinesterase by the (S)-enantiomer. Absolute configurations of the enantiomers were assigned on the basis of comparison with compounds of known configuration.