UC Davis

Recently, psychedelics have been gaining attention from both the public and the scientific community for their ability to provide fast-acting relief to a variety of detrimental neurological disorders. Previously, an array of different psychedelic scaffolds were utilized to treat mental disorders and it was discovered that each had the capacity to bring about positive effects within the affected patients. While relief to treatment resistant symptoms was achieved, undesired hallucinogenic side effects persist. For this reason, we were interested in exploring the pharmacology of psychedelics and to seek out the pharmacological signature of a hallucinogenic response within the serotonin receptors. Two alternative structure activity relationship (SAR) strategies were utilized to evaluate and compare synthetic analogs against parent scaffolds. A function-oriented synthetic (FOS) approach was employed on lysergic acid diethylamide (LSD). The tetracyclic LSD scaffold was de-rigidified and broken down to smaller subunits and then evaluated against serotonin2 (5-HT2) subtype selectivity for comparative purposes. In contrast, the flexible N,N-dimethyltryptamine (DMT) tail was conformationally rigidified with the goal of uncovering the biologically active conformer responsible for the hallucinogenic effect. Subsequently, we discovered two different scaffolds demonstrating enhanced selectivity within 5-HT2R subtype receptors. Additional focused SAR on rigidified DMT conformer revealed both enhanced activity at the 5-HT2A/C subtype receptors as well as suppressed activity at desired 5-HT2B subtype receptor. During the synthetic efforts, key novel strategies and methods like the Fischer Indole halogen blocking strategy were developed to selectively produce regioselective adducts from meta-substituted phenyl hydrazines.