title: The development of ultrashort acting neuromuscular relaxant tropane derivatives.
abstract: There is a need for neuromuscular relaxant (NMR) agents that are of the "nondepolarizing type" and produce rapidly developing and short-lasting skeletal muscle relaxation in anesthesiology. Many efforts have been directed to produce such agents. Our research focused on the design, synthesis, and evaluation of numerous "bisquaternary" derivatives of the cyclic aminoalkanes: tropane and granatane. Through systematic "steric structure-activity relationship" studies, we arrived at some new bisquaternary tropine and granatanol diesters, which in laboratory studies appeared to be the fastest and shortest acting NMRs recognized so far. Their ultrashort duration action-mechanism was, however, linked to the formation of nephrotoxic metabolites, precluding further development. Even so, we believe that the scientific information gained from more than a thousand such agents, will be useful toward developing the "ideal," ultrashort-acting NMR that could be clinically successful without the use of "reversing" agents, at least until "new biotechnology" may solve all problematic aspects of "transient" muscle relaxation.
authors.affiliation: Harbor-UCLA Medical Center and LA Biomedical Research Institute, Torrance, CA 90509, USA. laslogy@cox.net
authors.forename: Laszlo
authors.initials: L
authors.lastname: Gyermek
authors.forename: Chingmuh
authors.initials: C
authors.lastname: Lee
mesh_terms: D000762:Anesthesia Recovery Period; D000818:Animals; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005544:Forecasting; D006801:Humans; D008657:Metabolic Clearance Rate; D019148:Neuromuscular Blockade / Q000379:methods; D003473:Neuromuscular Nondepolarizing Agents / Q000737:chemistry* / Q000145:classification / Q000493:pharmacokinetics / Q000494:pharmacology*; D018579:Patient Selection; D013329:Structure-Activity Relationship; D013997:Time Factors; D014018:Tissue Distribution; D014326:Tropanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003473:Neuromuscular Nondepolarizing Agents; D014326:Tropanes; C512109:granatanol; C005864:tropine