GABA and Benzodiazepine Receptors I-II [antikvár]

INTRODUCTIONI. BEGINNINGSLike many other important discoveries, Eugene Roberts' discovery of GABA was serendipitous. In 1949, comparing the ninhydrin-positive substances in extracts of norma! brain and neuroblastoma cells, Roberts noticed a hitherto unobserved ninhydrin-positive spot, in extracts from mouse brain, but not in extracts of neuroblastoma cells. This spot was rather quickly identified as GABA. Despite Roberts' continuing efforts to interest neurophysiol-ogists in testing GABA on various neuronal preparations, about seven years elapsed before this was first done (in 1956). This fascinating story of accidental discovery and the subsequent follow-up leading to the identification of GABA as a neurotransmitter is told in detail in Volume 1, Chapter I.The discovery of specific [^H]-diazepam binding sites on rat brain membranes, in October 1976, was not entirely serendipitous. Reviewing my correspondence, 1 find a letter to Willy Haefely, (Hoffmann-LaRoche, Basle) dated August 6, 1976, in which 1 ask if he " would be able to provide us with a small portion of tritium labeled benzodiazepine, for ordinary in vitro affinity binding experiments." In another letter to Haefely dated September 20th, 1976, I wrote: "I was pleased to receive today a letter from two of your colleagues offering to provide me with 1 to 2 mCi of tritium labeled diazepam (specific activity 14.5 Ci/mMol) which will be quite sufficient for the experiments we would like to do. First, we intend to determine whether binding of labeled diazepam to a rat brain Pj fraction can be displaced by several of the unlabeled benzodiazepines which you sent us, by representative drugs, or by neurotransmitter candidates. We will send you the results as soon as they are available."In 1972 and 1973, mainly as a result of my discussions with Candace Pert, who was then a graduate student with Solomon Snyder at Johns Hopkins University, and then in the process of characterizing opiate receptors using radioligands, I started looking for radioligands for receptors in the brain as part of the psychotropic drug research program which we were developing at the Danish pharmaceurical firm Ferrosan A/S, located near Copenhagen. Radioligands for CNS receptors were quite rare in those days and our first was a ligand for muscarinic ACh receptors, [^H]-propylbenzilyl choline mustard ([^H]-PrBCM), which was a custom synthesis carried out for us by Amersham in England in 1975, using its allyl precursor synthesized by my colleagues at Ferrosan, J. A. Christensen and M. Engelstoft. This synthesis of [^H]-PrBCM had been worked out by A. S. V. Burgen et al. eariier' and we quickly confirmed the binding results of Burgen et al.'-^ using rat brain membranes. To my knowledge, I was the first in Denmark to use radioligands to characterize CNS receptors. While the [^H]-PrBCM project was a great success technically, and led me to intensify my efforts to obtain other radioligands, it yielded no surprises. Eventually we decided that the project was not going to result in the development of new psychotherapeutic drugs and we ended up giving away most of our [^H]-PrBCM to other investigators (see Reference 3 for an example).My visit to Hoffmann-La Roche in Basle, Switzerland, on July 20, 1976, which resulted in a generous gift of [^H]-diazepam from Willy Haefely, has been described previously.''When 1 hired Claus Braestrup on August 16, 1976, on a half-time basis, as an "editorial assistant", we had made no specific plans to study [^H]-diazepam binding. Braestrup's first assignment was to rewrite a manuscript on selective monoamine oxidase inhibitors (which was never published). About one month later, Braestrup, with great enthusiasm, threw all of his energy into my [^H]-naloxone project*^ which kept him quite busy until about the middle of December 1976.During our eariy work we failed to detect effects of GABA on ['H]-diazepam bind-