Magazine article Drug Topics

Splitting Pairs: Molecular Maneuver Aims for Better Drugs

Magazine article Drug Topics

Splitting Pairs: Molecular Maneuver Aims for Better Drugs

Article excerpt

Investigators have begun sorting out the molecules that make up synthetic drugs and drug candidates on the basis of a distinction that is seemingly so small, it might wrongly have been dismissed as insignificant.

Structurally identical, the molecules differ only in the way they are oriented in space. That is, they are nonsuperimposable, mirror images of each other. "Just as a glove is right-handed or lefthanded, a molecule can be 'righthanded' or 'left-handed,'" James Young, v.p. and general manager, pharmaceutical division, Sepracor Inc., told Drug Topics.

It turns out that these "enantiomers" or "optical isomers" can have very distinct properties, despite their matching structures. The differences between the sinister or left-handed molecules and the rectus or right-handed molecules of a compound called carvone can actually be tasted: The S-isomer tastes like caraway; the R-isomer, like spearmint.

Similarly, the different isomers contained in drug products may contribute dissimilar traits to compounds. The result can range from negligible to appalling. At one extreme, as with chloramphenicol or propranolol, a single isomer confers all the drugs' activity. Another example offered by Sepracor, is thalidomide. The R-isomer provided the drug's sedative effect. Its "evil twin," the S-isomer has been blamed for the terrible birth defects that are associated with the agent.

Enantiomers are not a recently identified phenomenon. Their existence was first confirmed by Louis Pasteur. But new technology is making it possible for the pharmaceutical industry to capitalize on a scientific observation that's nearly a century and a half old.

Chemists have recognized for quite a long time that compounds exist as a mixture of isomers, and, to some degree, they have also understood that the two forms could have different pharmacology, Young pointed out. "Chemically speaking, the difference (between optical isomers) is actually very subtle. What is important is that the biological systems recognize those differences as if they are two different compounds altogether," he added.

Like drug molecules, receptors can be "chiral" or possess the property of "handedness." One isomer in a compound may interact with the receptor in an ideal way," Young explained. Another may form a weaker connection with the same receptor. Or, it may lock into an unrelated receptor, thus causing unexpected or unwanted effects.

Not all drug products consist of a jumble of enantiomeric molecules. Agents found in nature generally occur in "pure isomer" form, Young pointed out. Some synthetic drugs were developed as a single isomer. For instance, the scientists who developed captopril and the other angiotensin-converting enzyme inhibitors had "quite a good understanding" of the structure of the receptor, he said. They knew that a pure isomer drug would provide an optimum fit with the chiral receptor.

Still, Young pointed out, in "a great majority of cases" where compounds contained a mixture of isomeric forms, it has been technologically difficult to produce the isomers in pure form in any quantity--especially the amounts needed for a commercial venture. "So," he added, "unless there was a compelling reason to develop only a purified form, most times in the past--the 1980s and earlier--companies have elected to develop the mixture."

At Sepracor, scientists are concentrating on single-isomer forms of drugs that are currently sold as a 50-50 blend of left-and right-handed molecules. Such compounds are called racemates. They are also studying some racemic agents that are still under investigation by major pharmaceutical companies. …

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