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

Abstract

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.

AB-CHMINACA, AB-PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9-Tetrahydrocannabinol–Like Effects in Mice

“…The profiles of AB-CHMINACA and FUBIMINA most closely matched those obtained previously with other synthetic cannabinoids, differing only quantitatively in their respective affinities, potencies, and efficacies. Similar to CP55,940 (present study) and other full dual CB 1 /CB 2 agonists (Huffman and Padgett, 2005), AB-CHMINACA and FUBIMINA displaced […”

“…In the present study, the in vitro positive control CP55,940 showed low nM K i for both CB 1 and CB 2 receptors, similar to a number of indole and pyrrole-derived synthetic cannabinoids (Huffman and Padgett, 2005;Wiley et al, 2014a). Furthermore, it stimulated [ 35 S]GTPgS turnover with high potency and efficacy at both receptors, suggesting that CP55,940 would act as a potent CB 1 receptor agonist in vivo.…”

Cytochrome P450-Mediated Oxidative Metabolism of Abused Synthetic Cannabinoids Found in K2/Spice: Identification of Novel Cannabinoid Receptor Ligands

“…[1-naphthalenyl-(1-pentyl-1H-indol-3-yl]-methanone (JWH-018) and [1-(5-fluoropentyl)-1H-indol-3-yl]-1-naphthalenyl-methanone (AM2201) represent two common derivatives structurally characterized as aminoalkylindoles (Compton et al, 1992a,b;Atwood et al, 2010). These derivatives were first synthesized in the early 1990s to study the pharmacology of the cannabinoid type 1 (CB 1 ) receptor, the predominant G-protein-coupled receptor in the brain, and the cannabinoid type 2 (CB 2 ) receptor, located on immune cells (Huffman and Padgett, 2005;Mackie, 2008). Receptor binding studies have shown JWH-018 (Atwood et al, 2010;Brents et al, 2011) and other aminoalkylindoles to be high-affinity ligands (Ward et al, 1990;Thakur et al, 2005) at CB 1 and CB 2 receptors.…”

Synthesis of Substituted Indenes through Iron‐Catalyzed Annulation of Benzylic Alcohols with Alkynes

“…[7c,8] Many biologically active natural products and pharmaceutically important compounds contain the indene skeleton. [9] Meanwhile, indenes are also extensively used as ligands in organometallics [10a-c] and as functional materials.…”