ABSTRACT
The present report describes development of hexamethonium complexes based on fullerene C60. Hexamethonium has a limited penetration into CNS and therefore can antagonize central effects of nicotine only when given at high doses. In the present studies conducted in laboratory rodents, intraperitoneal administration of hexamethonium-fullerene complexes blocked effects of nicotine (convulsions and locomotor stimulation). When compared to equimolar doses of hexamethonium, complexes of hexamethonium with derivatives of fullerene C60 were 40 times more potent indicating an enhanced ability to interact with central nicotine receptors. Thus, fullerene C60 derivatives should be explored further as potential carrier systems for polar drug delivery into CNS.
Subject(s)
Brain/drug effects , Fullerenes/pharmacokinetics , Hexamethonium Compounds/pharmacokinetics , Nicotinic Antagonists/pharmacokinetics , Aminocaproates/chemistry , Animals , Anticonvulsants/chemistry , Anticonvulsants/pharmacokinetics , Brain/metabolism , Dose-Response Relationship, Drug , Fullerenes/administration & dosage , Fullerenes/chemistry , Hexamethonium Compounds/administration & dosage , Hexamethonium Compounds/chemistry , Locomotion/drug effects , Male , Mice , Nicotine , Nicotinic Antagonists/administration & dosage , Nicotinic Antagonists/chemistry , Rats, Wistar , Seizures/drug therapyABSTRACT
Conformational and geometrical properties of the hexamethylenebis(trimethylammonium) (CH3)3N+-(CH2)6)-N+(CH3)3 (hexamethonium) and its derivatives with various degree of conformational flexibility of interonion chain having disulfide or two dimethylsilane groups or difluoromethylene chain instead of cholinesterase reversible inhibitors have been determined using molecular mechanics methods. Conformation-activity relationships between these inhibitors and different cholinesterases (human erythrocyte acetylcholinesterase, horse plasma butyrylcholinesterase, cholinesterase from the brain of the grass frog Rana temporaria and optical ganglia from the Pacific squid Todarodes pacificus and Comandor squids Berryteuthis magister from various areas) were investigated. Hypothesis of complex influence of conformational and geometrical properties (if molecules on anticholinesterase efficiency of compounds under investigation was formulated.
Subject(s)
Cholinesterases/drug effects , Hexamethonium Compounds/pharmacology , Invertebrates/enzymology , Vertebrates/metabolism , Animals , Chemical Phenomena , Chemistry, Physical , Cholinesterases/chemistry , Decapodiformes , Drug Interactions , Hexamethonium Compounds/chemistry , Horses , Humans , Molecular Conformation , Protein Conformation/drug effects , Rana temporariaABSTRACT
W84 (N,N,N',N'-tetramethyl-N,N'-bis-(3-phthalimidopropyl)-N,N'-hexane- 1,6- diyl-bis-ammonium dibromide) is a potent stabilizer of antagonist binding to muscarinic receptors; however, W84 hydrolyses in aqueous buffered medium. The synthesis of the stable derivative CHIN3/6 is presented containing a 2-phenyl-quinazolinone instead of the labile phthalimide substituent. This compound retarded [3H]N-methylscopolamine-dissociation in guinea-pig cardiac membranes with slightly higher potency than W84, the EC50 values amounting to 7.5 x 10(-7) and 13 x 10(-7) M, respectively. Molecular modelling revealed differences in the electron density of the substituents and in their molecular shape. It is suggested that the derivatives use partially different sites of attachment when occupying the allosteric binding site of the receptor protein.
