title: Effect of chirality and lipophilicity in the functional activity of evodiamine and its analogues at TRPV1 channels.
abstract: OBJECTIVE
  Evodiamine, a racemic quinazolinocarboline alkaloid isolated from the traditional Chinese medicine Evodiae fructus, has been reported to act as an agonist of the transient receptor potential vanilloid type-1 (TRPV1) cation channel both in vitro and in vivo. Evodiamine is structurally different from all known TRPV1 activators, and has significant clinical potential as a thermogenic agent. Nevertheless, the molecular bases for its actions are still poorly understood.
  
  
  METHODS
  To investigate the structure-activity relationships of evodiamine, the natural racemate was resolved, and a series of 23 synthetic analogues was prepared, using as the end point the intracellular Ca(2+) elevation in HEK-293 cells stably overexpressing either the human or the rat recombinant TRPV1.
  
  
  RESULTS
  S-(+) evodiamine was more efficacious and potent than R-(-) evodiamine, and a new potent lead (Evo30) was identified, more potent than the reference TRPV1 agonist, capsaicin. In general, potency and efficacy correlated with the lipophilicity of the analogues. Like other TRPV1 agonists, several synthetic analogues could efficiently desensitize TRPV1 to activation by capsaicin.
  
  
  CONCLUSIONS
  Evodiamine qualifies as structurally unique lead structure to develop new potent TRPV1 agonists/desensitizers.
authors.affiliation: Istituto di Cibernetica, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano Moriello
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fontana
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sacchetti
authors.forename: Daniele
authors.initials: D
authors.lastname: Passarella
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007536:Isomerism; D049990:Membrane Transport Modulators / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D004365:Drugs, Chinese Herbal; D049990:Membrane Transport Modulators; D011799:Quinazolines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; C049639:evodiamine
keywords: TRP channels; TRPV1; capsaicin; evodiamine; palvanil; vanilloids
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