When med颅ica颅tions linger in the human body, they some颅times pro颅duce toxic side?effects.

Pro颅fessor Alexan颅dros Makriyannis, the George D. Behrakis Trustee Chair in Phar颅ma颅ceu颅tical Biotech颅nology and Director of the Center for Drug Dis颅covery at North颅eastern, explained that many things can happen to a drug inside our bodies once it is ingested. For instance, the drug can be mod颅i颅fied into other byprod颅ucts with their own unde颅sir颅able and unpre颅dictable effects. Or it can remain embedded in the body??s fatty tis颅sues and then be slowly released into the cir颅cu颅la颅tory?system.

??If you had a way of con颅trol颅ling how long this drug sits in the body,?? Makriyannis said, ??that would be a ben颅e颅fi颅cial effect. It would be a safer?drug.??

In research recently pub颅lished in the Journal of Med颅i颅c颅inal Chem颅istry and Med颅i颅c颅inal Chem颅istry Let颅ters, Makriyannis and his team present not just one such drug but a whole series of them. ??We call this con颅cept?con颅trolled deac颅ti颅va颅tion,?? he explained.

In this research, Makriyannis?? team presents more than 100 com颅pounds that are vari颅ants of drugs the researchers pre颅vi颅ously patented. These new drugs target the endo颅cannabi颅noid system, which includes recep颅tors within the sur颅face of cells throughout our bodies that are respon颅sible for func颅tions like pain, mood, memory, and appetite modulation.

The orig颅inal ver颅sions of the new drugs bind to the cannabi颅noid receptors??which were ini颅tially named for their recog颅ni颅tion of the tetrahy颅dro颅cannabinol mol颅e颅cule found in marijuana??and pro颅duce some effects such as increased appetite or a sense of euphoria. How颅ever, the devel颅op颅ment of these drugs has been lim颅ited by the neg颅a颅tive side effects they elicit. In one high-????profile case, a cannabi颅noid antag颅o颅nist called Acom颅plia was designed to pro颅duce the oppo颅site effects of cannabis. The drug was intended to treat obe颅sity, but was pulled from the market when it was linked to increased sui颅cide?rates.

??Our lab works to design and make safer drugs with more con颅trol颅lable action,?? Makriyannis said. So with funding from the National Insti颅tute on Drug Abuse, he and his team set out to develop drugs that fea颅ture a timing mech颅a颅nism that would allow the drug to be deac颅ti颅vated as soon as it has per颅formed its func颅tion and be trans颅formed to inac颅tive products.

This timing mech颅a颅nism, Makriyannis said, is rel颅a颅tively simple??it just takes some very smart and spe颅cific chemistry.

The new drugs are chem颅i颅cally mod颅i颅fied to be biodegrad颅able and sus颅cep颅tible to par颅tic颅ular enzymes in the blood. The enzymes would rec颅og颅nize these drug??s new chem颅ical fea颅tures and ??chew them up?? right at that spot. The time it takes for the enzymes to finish their action can be con颅trolled, and the resulting byprod颅ucts from this enzy颅matic activity are com颅pletely safe, according to Makriyannis.

Addi颅tion颅ally, the drugs?? chem颅ical mod颅i颅fi颅ca颅tions ensure they don??t stick around in the body??s fatty tis颅sues as long, and are thus expelled much more?quickly.

??When we started making these new com颅pounds, we weren??t sure if they would be suc颅cessful,?? Makriyannis said. ??But actu颅ally, they worked even better than we??d hoped.?? Not only do the com颅pounds have fewer side effects than the orig颅inal ver颅sions of the drugs, they are also more potent and effective.

While the drugs in the present research all target recep颅tors in the endo颅cannabi颅noid system, the approach can be applied to vir颅tu颅ally any small-????molecule drug, Makriyannis said.

??We are con颅trol颅ling the fate of a drug by just designing these mol颅e颅cules in a manner that allows them to act pre颅dictably,?? he said. ??It??s a gen颅eral con颅cept that we??ve used to make anal颅gesic com颅pounds?that are safer and very potent, but the same con颅cept could be used to make neu颅ro颅pro颅tec颅tive drugs or other ther颅a颅peutic?agents.??