By David N. LeffScience Editor

By the time you're halfway through the main course at dinner, thefood you've already eaten has begun moving on from stomach to theupper small intestine. Stretched by the incoming bulk of partlydigested nourishment, the gut sends a signal to your brain that it'stime to stop eating.

This message travels upward, via the pneumogastric nerve, fromintestine to cerebral cortex, hypothalamus and limbic system, whichpass the word to the appetite-suppressing neurotransmitter,cholecystokinin 8 (CCK8).

No sooner has this molecule turned off your hunger pangs than anenzyme, cholecystokinase, pops up to terminate CCK8's anti-gluttony mission, by breaking down its eight-amino-acid chain.

The brains of grossly overweight people override this metabolicbalance between food intake and appetite satiation. That enzymekeeps them stuck in the "keep-on-eating" position.

For more than a decade, neuroscientists have sought ways and meansof preventing the enzyme from cutting short CCK8's activity, aspotential therapy for clinical obesity. One approach they consideredwas using the cholecystokinin molecule itself as a medicament.

This indication ran right up against two counter-indications: If takenorally, the neurotransmitter, being a peptide, never got past theintestine, which destroyed it before it had a chance to curb over-eating. If injected intravenously, it fell instant prey to peptidasecleavage.

In theory, finding a CCK8 analogue that resisted enzymaticdegradation was a promising goal, but in practice, researchers havenever found such a molecule.

At France's National Institute of Health and Medical Research(INSERM) in Paris, neuropharmacologist Jean-Charles Schwartzpictured another ploy: To make a drug that would demolish thatcholecystokinase enzyme before it could get in its licks againstCCK8.

Binational Partners Tackle Obesity-Drug Design

Schwartz heads a pharmacological neurobiology laboratory atINSERM. He is senior author of a paper in today's Nature titled:"Characterization and inhibition of a cholecystokinin-inactivatingserine peptidase."

It took him and his co-authors ten years to come up with such aninhibitor. To engineer this drug, they went into partnership withBritish medicinal chemist Robin Ganellin at University College,London.

For about five years between the late 1980s and early 1990s, Ganellintold BioWorld Today, the Upjohn Corp., of Kalamazoo, Mich.,funded this collaboration. It is now supported, he added, by a Paris-based biotechnology company, BioProjet.

"They are financing one post-doctoral research worker for me,"Ganellin said, "and some of Schwartz's people in Paris. The intentionis to put in the money for development when we identify a suitablecandidate compound."

The two teams' starting point, he recalled, "was to characterize thepresumed binding site of the enzyme to be inhibited by using simplyavailable dipeptides or tripeptides until one got the sense of someaffinity toward the lot."

Schwartz described their target enzyme to BioWorld Today as "atripeptidyl serine peptidase. It cuts the CCK8 octapeptide into threeparts _ two tripeptides, then a dipeptide. Needless to say," hepointed out, "all these compounds are biologically inactive."

The binational group named its candidate compound butabindide,which Schwartz explained, reflects its chemical derivation "from abutyl and an indoline."

Butabindide binds tightly and reversibly to the CCK8-attackingenzyme's active site, "thus inhibiting cleavage of its natural substrate,CCK8."

It also inhibits rodents from eating more than is good for them.

As described in Nature, the team starved mice for a full day, thenallowed them to consume short rations, not enough to assuage theirhunger.

Next, half of the cohort swallowed doses of butabindide, while theother half served as controls. All the still-ravenous animals then gotfree access to all the chow they could consume. The drug-dosedgroup ate only a third of what the controls gobbled down.

Since submitting their paper to Nature last November, Schwartz hasrepeated this experiment with rats. "It's well known," he toldBioWorld Today, that rats start to eat seriously at the end of the day,when darkness comes on. So we gave them the compound just beforeturning off the lighting, and measured the amount of food they tookduring the following hours. As with the mice, we saw a reduction ofabout 40 percent in their spontaneous food intake, compared tocontrol rats."

Even Phase I Human Trials `A Matter Of Years' Off

"We have plans for human trials of butabindide," Schwartz said, "butit takes quite a long time to assess the toxicity of the compound, andthen do Phase I and Phase II studies. At present," he added, "I cannotsay precisely, but it will probably be a matter of years even for thePhase I.

"Meanwhile, we are improving the compound, and starting to testsome of the new versions for toxicity in animals. These newcompounds differ slightly from butabindide," he observed, "butindeed we cannot talk too much on that at the present time."

Ganellin explained that "at the moment we are exploring additionalbinding sites to get increased in vivo potency. The gap between ourpresent butabindide and a suitable drug candidate is not a very bigone. It will probably take about a year's work to fill it."

He recalled that when the trans-channel drug-developmentcollaboration began, they faced an initial problem: "How do youreveal things that will clearly be patentable by going through normalgrant applications to government-funded committees, where it allbecomes public knowledge?"

Their deus ex machina came in the form of Upjohn. "Theyappeared," Ganellin said, "and invited our applications in aconfidential manner. We were delighted when they agreed to fundus."

Upjohn's subsequent withdrawal, he explained arose entirely "fromtheir own reorganization of research."

Butabindide and its successor molecules are quite different from therecently discovered obesity genes _ agouti, fat, ob, db, tub _ andtheir most promising therapeutic protein, leptin. (See BioWorldToday, Dec. 29, 1995, p. 1.)

"Our compound is a completely synthetic inhibitor of one enzyme,"Schwartz observed. n

(c) 1997 American Health Consultants. All rights reserved.