The development of cannabinoid receptor 1 (CB1) antagonists as pharmacotherapeutic agents for treating obesity and other metabolic disorders has been limited by their CNS-mediated adverse effects. However, selective antagonism of the peripheral CB1 receptors avoids CNS-mediated  side effects. One of our research interests is the identification and quantification of the structure-property relationships that distinguish peripherally-restricted CB1 antagonists/inverse agonists from conventional CNS-active CB1 blockers. We prepared a training set of 36 structurally-diverse compounds for which there was experimental evidence in the literature for peripheral restriction, strong CB1 binding and selectivity for CB1 over CB2 subtype. Analysis of this training set showed a wide range of topological polar surface area (TPSA) with poor correlation to CB1 binding affinity. This may be because some of the molecules are substrates of an active transport protein, such as P-glycoprotein, that effluxes these molecules from the CNS back into the periphery. Pharmacophore models built using this training set were observed to possess at least one hydrogen bond acceptor, one hydrophobic group and an aromatic ring. The highest-ranking pharmacophore model was a 4-point model with an additional aromatic ring feature. The best pharmacophore model from the present study will be used in virtual screening to predict novel peripherally-restricted CB1-selective antagonists.<br/>

Exploring the structural features of peripherally-restricted CB1 receptor antagonists and inverse agonists

255th National Meeting (2018)

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