The Sterling Research Group identified
pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory
pain reliever. As
drug design progressed, the ability of AAI analogs to block
prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the
CB1 cannabinoid receptor, a
G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computational chemistry methods to ultimately conclude that AAI and
cannabinoid ligands could overlap within a common binding pocket but that
WIN55212-2 primarily utilized steric interactions via aromatic stacking, whereas
cannabinoid ligands required some electrostatic interactions, particularly involving the CB1 helix-3
lysine. The Huffman laboratory identified strategies to establish
CB2 receptor selectivity among cannabimimetic
indoles to avoid their CB1-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic
pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as "Alkyl
Indole" receptors, and some AAI analogs act at the
colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the
CB1 receptor have found their way into the market as "Spice" or "K2". The sale of these alleged "herbal products" evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl
indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical
pharmaceutical companies that market medicines.