motional distress produces chemical changes in the body, which leads to depression and post-traumatic stress. This being so, then the one approach to treating these states could be drug therapy to control the body's chemistry. Those suffering the symptoms of these conditions display significantly enhanced levels of corticotropin-releasing factor (CRF) in their cerebrospinal fluid. CRF is a peptide hormone made up of 41 amino acids, and its job is to control the body's response to stress by releasing adrenocorticotropic hormone (ACTH).

   Nevertheless, ACTH release may not happen even though the body is trying to boost it by raising levels of CRF. This can be demonstrated by the intravenous injection of CRF and the lack of a response in the release of ACTH. It appears that if too much CRF is continually being produced, the body seems to ignore it. The answer then lies in finding an antagonist for CRF as a way of treating stress-related illness. Several CRF antagonists are known , but all of them are peptides, which means that they are unable to penetrate the blood-brain barrier and get to where they are most needed.

   Paper #6, by Yuhpyng Chen and colleagues of the Medicinal Chemistry and Neuroscience Department at Pfizer Inc., Groton, Connecticut, reports on a new non-peptide drug that overcomes this disadvantage. A screening program for compounds capable of binding to a particular CRF receptor uncovered a pyrazole molecule which displayed some activity, albeit rather weak. (Pyrazole is a five-membered heterocyclic aromatic ring with two nitrogens next to each other.) Starting with this simple clue, Chen's team then looked at other molecules that showed better structure-receptor relationships and which had better brain penetrability and oral bioavailability. The result was a pyrimidine derivative given the code name CP-154,526. This blocks CRF-induced elevation of ACTH and, in rats, shows marked antidepressant activity.

   Paper #6 describes how CP-154,526, can be made in the laboratory in 70% yield. The paper also reports on four chemically similar derivatives that the Pfizer group made, of which only one matched CP-154,526 in potency. Measurements were made in vitro using a radioactively labeled material, and then the agent was tested on stressed rats. The animals had been conditioned to link a bright light with a startling noise or an electric shock, and then were stressed by being subjected to the light alone. When the rats were given an injection of CP-154,526 they were clearly much better able to cope with the stress they were under.