C-Attached aminoalkylindoles: potent cannabinoid mimetics

D'Ambra, Thomas E.; Eissenstat, Michael A.; Abt, Jeffrey W.; Ackerman, James H.; Bacon, Edward R.; Bell, Malcolm R.; Carabateas, Philip M.; Josef, Kurt A.; Kumar, Virendra; Weaver, John D.; Arnold, Renée J.G.; Casiano, F; Chippari, Susan; Haycock, Dean A.; Kuster, Joan E.; Luttinger, Daniel; Stevenson, J. I.; Ward, Susan; Hill, Winfield; Khanolkar, Atmaram D.; Makriyannis, Alexandros

doi:10.1016/0960-894x(95)00560-g

Cited by 26 publications

(20 citation statements)

References 11 publications

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“…[27] The identification and quantification of the synthetic cannabinoids in such products demonstrates that currently a broad range of compounds circulates without any CB receptor binding data. As expected both compounds were present as racemates since it would be too expensive to use enantio-pure compounds for such products.…”

Section: Discussionmentioning

confidence: 99%

“…Biological testing of the individual stereoisomers in a [ 3 H]-CP-55940 cannabinoid binding assay demonstrated high enantioselectivity with approximately three orders of magnitude more potency for the more active enantiomer (Ki of the more active enantiomer vs. less active enantiomer: 0.27 nM : 217 nM). [27] The identification and quantification of the synthetic cannabinoids in such products demonstrates that currently a broad range of compounds circulates without any CB receptor binding data. In addition, the concentrations vary considerably between products and also between batches of the same product.…”

Section: Discussionmentioning

confidence: 99%

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Identification and quantification of synthetic cannabinoids in ‘spice‐like’ herbal mixtures: A snapshot of the German situation in the autumn of 2012

Langer

Lindigkeit

Schiebel

et al. 2013

Drug Testing and Analysis

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Synthetic compounds mimicking cannabis-like effects are a recent trend. Currently, these so-called synthetic cannabinoids are the largest and fastest growing class of newly appearing designer drugs. Many national authorities are continuously adapting their regulations to keep pace with the permanently changing variety of compounds. We have analyzed eight herbal smoking blends containing synthetic cannabinoids. Altogether, nine compounds could be identified, namely AM-2201, AM-2201-pMe (MAM-2201), AM-1220, AM-1220-azepane, UR-144, XLR-11, JWH-122-pentenyl, AM-2232, and STS-135. Newly appearing compounds were isolated by column chromatography and their structures elucidated by 1D- and 2D-nuclear magnetic resonance (NMR) experiments. In addition, the compounds were investigated by electron ionization-mass spectrometry (EI-MS) and electrospray ionization-tandem mass spectrometry (ESI-MS/MS) to complete the physicochemical dataset. Based on the purified compounds a universal gas chromatography-mass spectrometry (GC-MS) method was developed for the identification and quantification of these compounds in commercial smoking blends. By applying this method, up to five different compounds could be found in such products showing total concentrations from 72 to 303 mg/g smoking blend while individual compounds ranged from 0.4 to 303 mg/g. (1)H NMR spectra of the chiral compounds AM-1220 and its azepane-isomer recorded in the presence of 1 equivalent of (R)-(+)-α-methoxy-α-trifluoromethylphenylacetic acid (MTPA, Mosher's acid) showed them to be racemic mixtures.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification and quantification of synthetic cannabinoids in ‘spice‐like’ herbal mixtures: A snapshot of the German situation in the autumn of 2012

Langer

Lindigkeit

Schiebel

et al. 2013

Drug Testing and Analysis

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“…The Winthrop group reported well over 100 various cannabimimetic indoles, all of which belong to the subgroup of aminoalkylindoles [10,11,31,34]. These workers stated that the necessary criteria for CB 1 receptor affinity includes an aroyl group at C-3 of the indole, which, for maximum affinity should be 1-naphthoyl or substituted 1-naphthoyl.…”

Section: Cannabimimetic Indolesmentioning

confidence: 99%

Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes

Huffman¹,

Padgett²

2005

CMC

223

102

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During the development of new nonsteroidal anti-inflammatory agents, it was discovered that 1-aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB(1)) receptor. This has led to the development of over 100 cannabimimetic aminoalkylindoles, and the development of SAR for these compounds. Later work demonstrated that the aminoalkyl moiety was not necessary, and could be replaced by a four- to six-membered alkyl chain without loss of affinity. Investigation of these indoles led to the discovery of a CB(2) selective ligand, 3-(1-naphthoyl)-N-propylindole. Subsequent work has provided several additional CB(2) selective indoles. On the basis of a proposed pharmacophore for the cannabimimetic indoles, a series of pyrroles and indenes were developed, some of which are potent cannabinoids. SAR for several series of pyrroles have been developed. Two groups have described cannabimimetic indenes, which have been employed as rigid models for the receptor interactions of cannabimimetic indoles with the CB(1) receptor. There is some evidence that the indoles bind to a somewhat different site on the receptor than traditional cannabinoids, and interact with the receptor primarily by aromatic stacking.

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“…Although one can make generalizations regarding SAR at the CB2 receptor and concerning the structural features that lead to selectivity for the CB2 receptor, these generalizations are not even semi‐quantitative. For instance, it is known that an N ‐methyl‐2‐piperidinylmethyl substituent on the indole nitrogen enhances CB1 receptor affinity relative to a morpholinoethyl substituent ( D'Ambra et al , 1996 ), however the greater than 350‐fold increase in CB1 receptor affinity substituting an N ‐methyl‐2‐piperidinylmethyl group for the morpholinoethyl group present in AM1241 ( 29 ) would not have been predicted. Similarly, JWH‐015 ( 2 ) has K i =164±22 n M at CB1 receptor and K i =13.8±4.6 n M at CB2 receptor ( Huffman et al , 2005a ).…”

Section: Cannabimimetic Indolesmentioning

confidence: 99%

Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands

Poso

Huffman

2008

British J Pharmacology

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Recent developments indicate that CB2 receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB2 receptor and little affinity for the CB1 receptor. This review will discuss structure-activity relations at both receptors for classical cannabinoids and cannabimimetic indoles. Examples of CB2 selective ligands from both classes of compounds are presented and the structural features leading to selectivity are described. Two approaches, receptor mutations and molecular modelling, have been employed to investigate the interaction of ligands with both cannabinoid receptors. These results obtained from these techniques are discussed.

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C-Attached aminoalkylindoles: potent cannabinoid mimetics

Cited by 26 publications

References 11 publications

Identification and quantification of synthetic cannabinoids in ‘spice‐like’ herbal mixtures: A snapshot of the German situation in the autumn of 2012

Identification and quantification of synthetic cannabinoids in ‘spice‐like’ herbal mixtures: A snapshot of the German situation in the autumn of 2012

Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes

Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands

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