Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs

Date of Completion

January 2000


Health Sciences, Pharmacology|Chemistry, Pharmaceutical




This dissertation is focused on the development of cannabinoid receptor ligands with high affinity and selectivity, which would facilitate the characterization of cannabimimetic sites, the elucidation of biological functions of the cannabinoid system, and the therapeutic exploration of cannabinoid-based drugs. ^ We synthesized a series of iodinated covalent ligands with azido or isothiocyanato groups located at three different molecular regions, namely, the 1-indole moiety, the 3-indole aroyl group, and the 6-indole position, based on the lead compound 1-(N-methyl-2-piperidine)methyl-2-methyl-3-(2-iodo)benzoyl-1 H-indole (AM661). We then prepared another series of more potent affinity compounds. Of these, two second generation iodinated covalent ligands, AM2212 [Ki (nM), CB1/CB2: 1.4/18.9] and AM2213 [Ki (nM), CB1/CB2: 3.0/30], were further developed and proved to be highly potent for labeling cannabinoid CB1 and CB2 receptor respectively. ^ We developed a CB2 selective agonist AM1241 [K i (nM), CB1/hCB2: 548.4/1.6]. Its active enantiomer, R-(+)-AM1241, determined by both chiral synthesis and X-ray crystallography, displayed increased activity and selectivity. To provide sample for drug distribution study, the radioiodination method for AM1241 was investigated. AM1241 played an important role for uncovering the significance of the CB2 receptor. ^ To study the SAR of cannabimimetic 1,4-dihydro-1,2,4,5-tetrazines, several synthetic methods were explored. Using diazonium salts or phenyl hydrazine, hydrizino chlorides were prepared and subsequently dimerized to symmetrical and/or nonsymmetrical tetrazine analogs under different basic conditions. Base promoted dimerization of the ethyl diazoacetate provided an alternative method to synthesize tetrazine analogs. SAR analysis of thirty tetrazine analogs indicated that a minor structural change would lead to the significant decrease of either activity or selectivity. ^ We identified a highly active radioligand 1-(N-methyl-2-piperidinyl)methyl-3-(2-iodo)benzoy]-1 H-indole [AM2233, Ki (nM), CB1/CB2: 3.4/7.6] for autoradiography study of the brain CB1 receptor. AM2233 behaves as a full agonist and [131I]-AM2233 was preferentially localized at CB1 receptor rich areas in the mouse brain. AM2233 was resolved, and both of its enantiomers were radioactively labeled for further investigation. ^ Efforts to develop CB1 selective ligands are the ongoing project. Several high affinity compounds with certain selectivity for CB1 receptor have been synthesized and two new structures along with their synthesis are proposed. In addition, a synthetic route for solution/solid phase synthesis of symmetrical/nonsymmetrical tetrazine analogs is designed. If successful, it will assist greatly the automation and parallel synthesis of tetrazine analogs. ^