One of the biggest issues in terms of using Cannabis to treat any disorder is that it produces an intoxicating effect. The intoxicating effects are due to THC binding to the orthosteric site of the type 1 cannabinoid receptor (CB1). It is hypothesized that the intoxicating properties of CB1 activation can be avoided if a drug bound to the allosteric site (i.e. separate or “other”) on the receptor to promote endogenous activation but not directly activate CB1. This is how we propose to create CB1-targeted therapies. The allosteric modulators that will be evaluated are positive allosteric modulators (PAMS) or negative allosteric modulators (NAMS). A PAM enhances the effect of the primary ligand while a NAM reduces the effect of the primary ligand. The Laprairie research group collaborates with Dr. Ganesh Thakur (Northeastern University) to obtain potential allosteric modulators.<br/><br/>With the potential PAM’s we work with there are 2 main structural considerations (1) enantiomeric differences (2) substituent effects. Previous research shows that GAT591 behaves as an ago-PAM. It is thought that one of the enantiomers is attributed to its agonist activity while the other its PAM activity. Thus far 13 GAT compounds have been evaluated via radioligand binding assay to measure (1) orthosteric affinity and (2) whether the compound behaves as a PAM or agonist. Preliminary findings are that the S enantiomer produces PAM activity while the R enantiomer produces agonist activity.<br/><br/>The purpose of the above 3 compounds is to see what pharmacological effect moving the fluorine atom from one ring to another has. Because the substituent changed is the same in each case, we can see if the position dictates activity. Preliminary findings are that all 3 compounds behave as weak PAM’s of which GAT605 is the strongest and GAT613 is the weakest. Similarly placing nitrogen inside each of the benzene rings does not change the activity of the compound.

Activity of enantiomeric derivatives of GAT 211

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.