By David N. Leff

Extremely high-dose injections of caffeine caused bizarre dancing movements in mice,for all the world like the involuntary, arrhythmic, unpatterned limb motions ofHuntington's chorea patients. One selective adenosine receptor agonist diminished thischoreiform locomotor activity; another did not.

Caffeine, like theophylline in tea and theobromine in chocolate, is an antagonist toadenosine.

Pharmacologist Olga Nikodijevic of the National Institute of Diabetes, Digestive andKidney Diseases (NIDDK) will present her dancing-mice experiment this November inWashington, D.C. at the 23rd annual meeting of the Society of Neuroscience. Her reportsuggests that “these animals could be used as a model for ... possible therapeuticapproaches to ... Huntington's disease or Tourette syndrome.“

Adenosine Research Mushrooming

Her co-author, Kenneth Jacobson, who heads the molecular recognition section of NIDDK'slaboratory of bioorganic chemistry, synthesized the agent that reversed theHuntington-like effects in the mice. Jacobson is a leading investigator in what he calls“the mushrooming field of adenosine research.“ (At the upcoming Neurosciencemeeting, for instance, fully 42 papers and posters have “adenosine“ in theirtitles).

Jacobson has just sent the Federal Register a notice advertising for anindustrial partner to help elaborate “The Biomedical Use of AdenosineDerivatives,“ under a CRADA.

Specifically, NIDDK “seeks an agreement with a pharmaceutical company for thejoint research, development, evaluation and possible commercialization of possibleagonists and antagonists of adenosine-A₁ and adenosine-A₂receptors.“ These receptors are the keys that unlock the molecule's ubiquitousactivity.

“The original interest in adenosine receptors,“ Jacobson told BioWorld,was as anti-hypertensive agents. “But it's branched out into much more than that,because there are so many sites in the body at which these adenosine receptorsoccur.“ His list of such sites, the disease states that afflict them, and thepotential of the A-word derivatives for treating them, sounds like the pitch of anold-time snake oil vendor.

Jacobson's CRADA announcement lists the “potential therapeutic aspects of agonistsand antagonists of adenosine derivatives implicated as effective agents for hypertension,pain control, selective cognition-enhancement, anti-asthmatic activity, cystic fibrosis,central nervous system disorders (Alzheimer's, Parkinson's and Huntington's diseases;epilepsy), stroke protection, kidney protection, cardiovascular diseases, modulation ofimmune responses.“

Beating Bushes for a Collaborator

“Our own lab,“ Jacobson said, “is developing compounds from thediscovery stage, where we actually think up what structures to make, and then go ahead andsynthesize a whole series through in vitro screening. Then we take it all the wayinto animals.“ Now he is beating the bushes for an industrial CRADA collaborator totake the adenosine opportunity into clinical trails and eventual pharmaceutical products.

Getting in on this ground floor of adenosine R&D -- a space that is getting moreand more crowded -- will offer the prospective ally “rights of first negotiation forlicensing government rights to any subject inventions arising under the agreement.“The chosen candidate “will provide research staff support and advance funds ... tohelp defray government expenses for patenting such invention.“

Jacobson over the past decade has acquired three issued patents for adenosine-relatedinventions, plus four allowed, five pending and one appealed. All are available forlicensure under the proposed CRADA.

For most of the past 10 or 15 years that scientists have been exploring adenosine,Jacobson observed, “it's been known that there are A₁ and A₂receptors: A₁ slows the heart rate; A₂ causes vasodilation; togetherthey lower blood pressure.“

Now, he said, “through cloning techniques, people have found a third adenosinereceptor, A₃, which occurs in heart, testes and brain.“

Last month at the American Chemical Society meeting in Chicago, Jacobson's groupreported on the first selective agonist for A₃ receptors, which has 14-foldselectivity.

The “exceptional preclinical progress, both chemical and biological“ Jacobsonconceded, “has not been paralleled in the clinic.“ The only approved compoundknown to produce its therapeutic actions via adenosine receptors, he points out, “isadenosine itself,“ to treat supraventricular tachycardia. FDA-designated it as“a drug for a major unmet medical need.“