Aminoalkylindoles: Structure-Activity Relationships of Novel Cannabinoid Mimetics

Abstract

Aminoalkylindoles (AAIs) are a novel series of cannabinoid receptor ligands. In this report we disclose the structural features of AAIs which are important for binding to this receptor as measured by inhibition of binding of [3H]Win 55212-2 (5). Functional activity in the mouse vas deferens is also noted and used to distinguish agonists from potential antagonists. The key structural features for potent cannabinoid activity in this series are a bicyclic (naphthyl) substituent at the 3-position, a small (H) substituent at the 2-position, and an aminoethyl (morpholinoethyl) substituent at the 1-position. A 6-bromo analog, Win 54461 (31), has been identified as a potential cannabinoid receptor antagonist. Modeling experiments were done to develop a pharmacophore and also to compare AAI structures with those of classical cannabinoids. The fact that the cannabinoid AAIs arose out of work on a series of cyclooxygenase inhibitors make sense now that an endogenous cannabinoid ligand has been identified which is a derivative of arachidonic acid. Because of their unique structures and physical properties, AAIs provide useful tools to study the structure and function of the cannabinoid receptor(s).

Baths Salts, Spice, and Related Designer Drugs: The Science Behind the Headlines

“…WIN55212-2, an aminoalkylindole, was the template for synthesis of the original series of indole-derived synthetic cannabinoids (Eissenstat et al, 1995;. Subsequent studies reported an orderly structure-activity relationship between structural variation in these molecules (e.g., length and branching of the chain) and cannabinoid binding (Huffman et al, 1994;Lainton et al, 1995;Aung et al, 2000) and, when tested, in vivo cannabimimetic activity (Wiley et al, 1998(Wiley et al, , 2012a(Wiley et al, , b, 2014a.…”

In Vitro Metabolism ofR(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a Cannabinoid Receptor Agonist

“…2 ) are a structurally distinct group of cannabinoid receptor agonists that were originally developed from pravadoline Bell et al, 1991;D'Ambra et al, 1992;Kuster et al, 1992;Eissenstat et al, 1995). AAIs have been found to displace potent cannabinoid ligands such as CP-55940 in competitive binding to the CB1 cannabinoid receptor .…”

Modulation of Excitatory Synaptic Transmission by Δ9-Tetrahydrocannabinol Switches from Agonist to Antagonist Depending on Firing Rate

“…In addition to its low intrinsic activity, THC is highly lipophilic, which imbues it with properties incompatible with many experimental techniques, including poor washout and insufficient penetration of brain slices (Lundberg et al, 2005;Lovinger, 2008). Thus, more water-soluble full CB1 agonists such as Win55212-2 are widely used for in vitro studies (Eissenstat et al, 1990). …”