Improvement on the Antitussive Activity of NTI

This cough model was used to determine SARs of NTI derivatives. In addition to the antitussive efficacy of compotmds, it is possible to assess not only compounds intrinsic affinity for the receptor but their absorption, distribution, metabolism, and excretion (ADME) properties. 

Improving a drug s permeability through the BBB can enhance its concentration in the CNS. Therefore, improving the BBB permeability of NTI might augment its antitussive activity. 

The BBB consists of microcapillary blood vessels that mn throughout the brain in close proximity to brain cells [37, 38]. On the inner surface of the capillaries, the endothelial cells are held tightly together to each other to form a monolayer. Centrally acting drugs must permeate through these endothelial cells to penetrate into the brain. 

In general, the physicochemical properties of a compound can greatly affect its capacity for passive transcellular BBB permeation. General strategies for modifying drug stmctures to improve BBB permeability include the following [37, 38]  

In addition to passive transport, active transport can occur with proteins lodged in the BBB that facilitate uptake and efflux of compounds into and out of the CNS. Therefore, compounds can be modified to enhance their affinity for uptake transporters or reduce their affinity for efflux transporters e.g., R-glycoprotein) to improve BBB permeability [37]. However, these strategies required major structural transformations thus, we focused on strategies related to changing the physicochemical properties of NTl, as mentioned below. 

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