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Last dance with Mary Jane

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April 02, 2014

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They call it “get­ting high” for a reason. The tetrahy­dro­cannabi­noid mol­e­cule, or THC, con­tained in mar­i­juana gives its users a legit­i­mate feeling of bliss. In addi­tion to its recre­ational use, 20 states have legal­ized the sale of med­i­c­inal mar­i­juana, with advo­cates citing its ability to alle­viate pain in cancer patients and bring com­fort to vet­erans suf­fering from PTSD.

Still, health pro­fes­sionals are quick to note that mar­i­juana has plenty of draw­backs, including its addic­tive qual­i­ties, its capacity to cloud your memory, and its asso­ci­a­tion with binge eating. That’s why North­eastern assis­tant pro­fessor of phar­macy   Ganesh Thakur wants to create alter­na­tive com­pounds that have the same med­i­c­inal ben­e­fits as THC without these asso­ci­ated side effects.

THC, or cannabis, lends its name to the recep­tors on which it acts. Dis­cov­ered in the 1980s, the cannabi­noid recep­tors CB1 and CB2 are located on com­plex pro­teins embedded in the cell mem­branes of some parts of the brain and other organs. When the recep­tors are bound, the pro­tein changes shape, allowing pleasure-​​inducing neu­ro­trans­mit­ters such as dopamine to pass through.

THC is just one member in a large class of mol­e­cules that trigger this phe­nom­enon. There are at least 80 more “endo­cannabi­noids” that nat­u­rally occur in the body. Many researchers have focused on devel­oping syn­thetic cannabi­noids that either stim­u­late or repress the response. But, as Thakur pointed out, syn­thetic cannabi­noids bring with them the same neg­a­tive side effects as marijuana.

My lab­o­ra­tory is trying to develop effec­tive and safer med­ica­tions for treat­ment of dis­eases that rep­re­sent unmet med­ical needs,” Thakur said. “We work on tar­gets that are val­i­dated for cer­tain dis­eases but drug devel­op­ment hasn’t suc­ceeded because of the side effects.”

While CB1 and CB2 are the recep­tors through which pot pro­duces its med­ical and psy­chotropic activity, the com­plex pro­teins men­tioned ear­lier also sport a number of other recep­tors. These so-​​called “allosteric” recep­tors get their name from the Greek words “allos” and “stereos,” which, Thakur said, roughly trans­late to “other sites.”

When allosteric recep­tors are bound, he explained, the pri­mary cannabi­noid recep­tors change shape, thereby increasing or decreasing their activity with the nat­u­rally occur­ring cannabinoids.

Thakur said the approach could be applied in a variety of ways. He envi­sioned the devel­op­ment of a drug that treats anorexia by increasing food-​​related plea­sure without the side effect of addic­tion. Another poten­tial drug could treat obe­sity by curbing that desire without causing sui­cidal tendencies—the main problem with sim­ilar drugs that bind CB1 and CB2 directly.

Thakur is also applying his approach to create safer, more effec­tive phar­ma­ceu­ti­cals that have the cognition-​​enhancing effects of nico­tine without its addic­tive properties.

These are tar­gets that have been val­i­dated but have had no suc­cess in phar­ma­ceu­tical pro­grams because of the side effects,” Thakur said. “We’re trying to think of dif­ferent ways of taking the same target and tuning it to be selec­tive and safe.”

- See more at: http://www.northeastern.edu/news/2014/03/thakur/#sthash.pyjS7dHS.dpuf

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