title: Argyreia nervosa (Burm. f.): receptor profiling of lysergic acid amide and other potential psychedelic LSD-like compounds by computational and binding assay approaches.
abstract: BACKGROUND
  The convolvulacea Argyreia nervosa (Burm. f.) is well known as an important medical plant in the traditional Ayurvedic system of medicine and it is used in numerous diseases (e.g. nervousness, bronchitis, tuberculosis, arthritis, and diabetes). Additionally, in the Indian state of Assam and in other regions Argyreia nervosa is part of the traditional tribal medicine (e.g. the Santali people, the Lodhas, and others). In the western hemisphere, Argyreia nervosa has been brought in attention as so called "legal high". In this context, the seeds are used as source of the psychoactive ergotalkaloid lysergic acid amide (LSA), which is considered as the main active ingredient.
  
  
  OBJECTIVE
  As the chemical structure of LSA is very similar to that of lysergic acid diethylamide (LSD), the seeds of Argyreia nervosa (Burm. f.) are often considered as natural substitute of LSD. In the present study, LSA and LSD have been compared concerning their potential pharmacological profiles based on the receptor binding affinities since our recent human study with four volunteers on p.o. application of Argyreia nervosa seeds has led to some ambiguous effects.
  
  
  METHODS
  In an initial step computer-aided in silico prediction models on receptor binding were employed to screen for serotonin, norepinephrine, dopamine, muscarine, and histamine receptor subtypes as potential targets for LSA. In addition, this screening was extended to accompany ergotalkaloids of Argyreia nervosa (Burm. f.). In a verification step, selected LSA screening results were confirmed by in vitro binding assays with some extensions to LSD.
  
  
  RESULTS
  In the in silico model LSA exhibited the highest affinity with a pKi of about 8.0 at α1A, and α1B. Clear affinity with pKi>7 was predicted for 5-HT1A, 5-HT1B, 5-HT1D, 5-HT6, 5-HT7, and D2. From these receptors the 5-HT1D subtype exhibited the highest pKi with 7.98 in the prediction model. From the other ergotalkaloids, agroclavine and festuclavine also seemed to be highly affine to the 5-HT1D-receptor with pKi>8. In general, the ergotalkaloids of Argyreia nervosa seem to prefer serotonin and dopamine receptors (pKi>7). However, with exception of ergometrine/ergometrinine only for 5-HT3A, and histamine H2 and H4 no affinities were predicted. Compared to LSD, LSA exhibited lower binding affinities in the in vitro binding assays for all tested receptor subtypes. However, with a pKi of 7.99, 7.56, and 7.21 a clear affinity for 5-HT1A, 5-HT2, and α2 could be demonstrated. For DA receptor subtypes and the α1-receptor the pKi ranged from 6.05 to 6.85.
  
  
  CONCLUSIONS
  Since the psychedelic activity of LSA in the recent human study was weak and although LSA from Argyreia nervosa is often considered as natural exchange for LSD, LSA should not be regarded as LSD-like psychedelic drug. However, vegetative side effects and psychotropic effects may be triggered by serotonin or dopamine receptor subtypes.
authors.affiliation: Institute of Legal Medicine, Goethe University of Frankfurt/Main, Kennedyallee 104, D-60596 Frankfurt/Main, Germany. paulke@em.uni-frankfurt.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Paulke
authors.forename: Christian
authors.initials: C
authors.lastname: Kremer
authors.forename: Cora
authors.initials: C
authors.lastname: Wunder
authors.forename: Janosch
authors.initials: J
authors.lastname: Achenbach
authors.forename: Bardya
authors.initials: B
authors.lastname: Djahanschiri
authors.forename: Anderson
authors.initials: A
authors.lastname: Elias
authors.forename: J Stefan
authors.initials: JS
authors.lastname: Schwed
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Toennes
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D027722:Convolvulaceae / Q000737:chemistry*; D004874:Ergonovine / Q000494:pharmacology; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D009116:Muscarine / Q000378:metabolism; D011619:Psychotropic Drugs / Q000737:chemistry / Q000494:pharmacology*; D011941:Receptors, Adrenergic / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012639:Seeds / Q000737:chemistry
chemical_list: D011619:Psychotropic Drugs; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D011968:Receptors, Histamine; D011985:Receptors, Serotonin; D009116:Muscarine; D008238:Lysergic Acid Diethylamide; D004874:Ergonovine