Researchers searching for a compound that could block the addictive effects of cocaine may have overturned an unwritten law of neurological drug design. For many years, scientists have assumed that drugs designed to target the brain have to contain nitrogen, because almost all molecules known to transmit signals between brain cells contain the element. Now neuroscientist Bertha Madras of Harvard Medical School in Boston and synthetic chemist Peter Meltzer of Organix Inc. in Woburn, Massachusetts, and their colleagues have found that compounds in which the traditional nitrogen is replaced with oxygen can bind to the same brain receptors as does cocaine--and the nitrogen-based prescription drugs Ritalin and Prozac, prescribed for hyperactivity and depression.
The work, described in the December issue of Synapse, not only broadens the possibilities for finding new compounds effective in the brain, says Madras, but it may also help scientists better understand how neurotransmitters--the compounds that carry brain signals--bind to their targets. According to Ivy Caroll, a medicinal chemist at Research Triangle Institute in North Carolina, the finding suggests that combinatorial chemists--who assay thousands of compounds at once looking for useful drugs--should "take another look at non-nitrogen-containing compounds."
Madras and Meltzer happened on their discovery while trying to design a compound that would bind to brain molecules called transporters, which absorb and recycle neurotransmitters like dopamine, serotonin, and norepinephrine. Cocaine binds tightly to the dopamine transporter, blocking the reuptake of dopamine and enhancing the signals it sends. A compound that bound more loosely, they thought, might prevent cocaine from blocking the transporter but still allow it to take up dopamine. And because the positive electric charge that nitrogen bears was thought to be crucial to tight binding, Madras and Meltzer decided to try oxygen-containing compounds. To their surprise, however, they found in test-tube experiments that some of their "nonamines" blocked the transporter even more strongly than did nitrogen-based counterparts.
The finding means that the compounds won't help against cocaine addiction. But it may reveal a new mechanism by which compounds bind to neurotransmitter receptors, says Caroll. And it suggests, says Madras, that a whole realm of brain chemistry, including new classes of oxygen-containing neurotransmitters, may be awaiting discovery.