By Dean A. Haycock

Special to BioWorld Today

The neuropeptide substance P has long been associated with pain in lab animals and humans. Corporations have felt some pain associated with substance P, too.

For nearly two decades, various pharmaceutical companies have sought therapeutic applications for compounds that block the actions of the 11-amino-acid peptide. In addition to pain, substance P antagonists have been proposed as treatments for inflammation, asthma and emesis.

"Psychiatric disorders were always on the list, but it was a much more difficult area to define exactly which patient population would be appropriate," said Nadia Rupniak, a senior investigator at the Merck Sharp & Dohme Neuroscience Research Centre, in Harlow, England.

While substance P antagonists look promising as potential treatments for chemotherapy-induced vomiting, they have proven to be disappointments as pain relievers.

Of course, there are different types of pain. Could substance P play a role in mediating psychological or emotional pain as well as physical pain? Depression and anxiety are two prime examples of disorders that might be described as producing troubling and in many cases, debilitating emotional pain. Although substance P previously had been linked to stress in animals, there was no strong indication that an antagonist might work in depression. Nevertheless, scientists at Merck research facilities in England and in the U.S. — as well as clinical researchers in four U.S. cities — thought the question was worth answering.

Encouraging results from animal experiments and from human clinical trials conducted by Merck researchers and their collaborators now suggest that substance P might indeed play a role in "emotional" pain. The evidence appears in "Distinct Mechanism for Antidepressant Activity by Blockade of Central Substance P Receptors," an article in the Sept. 11 issue of Science.

"This has been an enormous collaborative effort across Merck worldwide and also across academic study centers where the clinical trials were done," Rupniak said.

Rupniak, the principal contributor for the preclinical studies described in the report, and her colleagues realized that the usual animal models for studying antidepressants affecting monoamine neurotransmitters in the brain were not appropriate for substance P research. The Merck researchers realized they needed a different test system.

First Positive Data Began To Appear Two Years Ago

"We were actually banging our head against a brick wall, as other people were for a very long time before that, trying to figure out what these non-peptide substance P antagonists might be useful for," Rupniak said.

The high affinity of MK-869 and a related compound for gerbil and guinea pig substance P receptors suggested that these rodents — not the most conventional in the field — might be good test subjects for this type of study.

Guinea pig pups emit cries when isolated from their litter mates. These cries are induced by substance P agonists, and inhibited by available antidepressant and anxiety-relieving medications. The ability of the Merck compound MK-869 to antagonize these cries and to block a substance P-induced "foot tapping" motor behavior in gerbils strongly suggested that the compound blocks substance P receptors in vivo. Furthermore, MK-869 improved the ability of another antidepressant drug, fluoxetine, to produce "antidepressant-like profiles" in animal models.

"If you look at the neuroanatomical distribution of the monoamine pathways, you can see that they have a very widespread distribution throughout the brain, as does substance P," Rupniak told BioWorld Today. "These pathways converge on common parts of the brain, such as the amygdala, which are known to be very important for regulation of emotionality. It is possible that these agents are acting through common neural substrates, but we don't have direct evidence that addresses that right now."

Preclinical experiments produced solid evidence that the Merck compound blocked substance P receptors. Experiments in humans indicated that the compound might not only lead to a promising treatment for depression but for anxiety as well.

The clinical trials lasted six weeks and included over 200 outpatients with major depressive disorder and moderately high levels of anxiety. Drug effectiveness was determined using two standard psychological tests for evaluating depression and one for evaluating anxiety.

The effects of the substance P antagonists were compared with a placebo treatment and with paroxetine, an marketed antidepressant.

MK-869 not only relieved symptoms of depression as well as paroxetine but reduced indications of anxiety as well.

Mark Kramer, senior research physician at Merck Research Laboratories, in West Point, Pa., said one encouraging factor was "the robustness and consistency of the response from center to center, indicating, at least in this initial study which needs to be replicated, that we are looking at a mechanism which people perceive across various investigative centers."

Well tolerated, the Merck compound produced fewer side effects than paroxetine. Only 3 percent of the subjects taking MK-869 reported sexual dysfunction, compared to 26 percent taking the other antidepressant.

If substance P antagonists do turn out to be effective antidepressants, they will represent the first class of such drugs in 40 years that do not work by directly affecting monoamine neurotransmitter systems, according to a Merck press release.

"When you have a mechanism like this, which is not working through the classic mechanisms of monoamines like norepinephrine or serotonin, and you see this kind of response, the hopes run high that you are actually going to see something as the study continues that is unusual," said Kramer, who was the principal contributor for the clinical studies described in the Science paper.

The development of MK-869 or a related compound for treating depression would also represent the first time in 40 years that Merck has ventured into the field of neuropsychiatric therapeutics. The last time was in the late 1950s, when Merck introduced two tricyclic antidepressant drugs, amitriptyline and protriptyline.

Merck is considering testing MK-869 in patients diagnosed with anxiety disorder and other major psychiatric illnesses. *