Design and Synthesis of Novel CNS Biological Probes

Abstract

Agents that exert their effects in the central nervous system are among the most important in medicinal practice. One in three Americans will have a disease affecting the nervous system in their lifetime exceeding $600 billion dollars per year in cost. Side effects, lack of efficacy, and lack of selectivity hamper their clinical use. Thus, additional agents need to be developed and new chemical tools are needed to further elucidate the mechanisms of CNS disorders. Salvinorin A, the main component of the hallucinogenic mint Salvia divinorum is a novel and potent ê opioid (KOP) receptor agonist that is the first naturally occurring opioid ligand that lacks a basic nitrogen atom. In efforts to attain a greater understating for the interatctions of the furan ring binding pocket within the KOP receptor, several modifications were made at the C-13 position of the salvinoirn A scaffold. Pharmacological evaluations of the synthesized analogues indicated that there is a prefferred orientation of the furan O-atom in that the cis alkene analogue (236) had a greater binding affinity than the trans alkene analogue (235). However, despite its similar binding affinity to that of salvinorin A the cis analogue showed to 34-fold less active than salvinorin A. It was also hypothesized that a combination of the salvinorin A scaffold with a similar terpene based family of marine natural products, namely the nakijiquinones, will alter the biological activity of salvinorin A and yield a useful biological probe. With this hypothesis in mind, several quinone containing salvinoirn A analogues were synthesized and upon pharmacological evaluation it was determined that these analogues did not exhibit any significant KOP receptor activity, indicative of a change in the biological activity of the salvinorin A scaffold. Furthermore, these analogues proved to be the first salvinorin A based analogues that exhibit antiproliferative activity. In the search for novel CNS biological probes, the aminoalkylindole class of synthetic cannabinoids was also investigated. Due to its cannabinoid 1 receptor (CB1R) antagonist activity, JWH-073-M4 was shown to be a valuable lead molecule. The hypothesis was that the design and synthesis of JWH-073-M4 based analogues would lead to compounds with dual CB1R antagonist/CB2R agonist activity that may have potential as alcohol abuse therapies. Upon in vitro pharmacological investigation, two analogues 461 and 444 were shown to have the most promise and were further subjected to in vivo pharmacological evaluation in animal models of alcohol abuse, namely ethanol self-administration and ethanol conditioned place preference. From these studies it was determined that analogues 461 and 444 exhibit dual CB1R antagonist/CB2R agonist activity and represent potential leads in the ongoing search for novel alcohol abuse therapies.