From: nobody@REPLAY.COM (Anonymous) Subject: Re: valium (NOT DERIVED FROM VALERIAN!) Date: 1997/05/22 Newsgroups: alt.drugs.hard,alt.drugs.chemistry,alt.drugs,rec.drugs.misc > >AFAIK, valium is a synthetic that is based on valerian root extract. > > Sorry but that's an urban myth! > > Mike From "The benzodiazepine story" by Leo H. Sternbach: (Prog Drug Res, 1978, 22:, 229-66) The story started in the mid-fifties when it became apparent that a new class of therapeutic agents, the tranquilizers, were of considerable clinical value, and our company [Roche] decided to enter this area of research. The pharmacological tests for the screening of sedatives and tranquilizers were well in hand and we chemists were asked to produce a novel compound which would have the desired properties, would be patentable, and, last but not least, would be superior to the then existing tranquilizers. A chemist confronted with such a problem has a variety of possibilities at his disposal. He can resort to the old, but very successful approach of molecular modification, sometimes disparagingly called molecular manipulation, which is based on the synthesis of compounds structurally related to biologically active products, and has resulted in a multitude of drugs superior to their prototypes. The modification or simplification of the molecular structure of naturally occurring alkaloids, hormones and antibiotics gave the desired result in many cases...This approach did not seem particularly promising to us, since the then known tranquilizers were intensively studied by several groups of investigators, i.e meprobamate (Miltown(R)) at the Wallace Laboratories, reserpine by the Ciba research group, and chlorpromazine by the research team at the S.K.F Laboratories. Another possible approach would be to use as starting point a biochemical working hypothesis leading to the synthesis of compounds fulfilling certain structural criteria. This, however, offered considerable difficulty, since practically nothing was known at that time about the chemical processes occurring in the brain. It was therefore decided to attack the problem in a different manner and to select an aproach which was most attractive to the organic chemist and would offer the most interesting chemical problems. We planned to look for a completely new type of tranquilizer and to work with a new class of compounds not known to possess any biological properties. [...] In the search for such a class of compounds, I recalled some products I had encountered during my Cracow assistantship years in the early thirties. At that time, we were looking for new azo dyes or interesting novel dyestuff intermediates and came across some products known in the German literature as 4,5-benzo-[hept-1,2,6-oxdiazines]. They were chemically rather attractive, were formed in good yield, underwent some interesting chemical reactions but unfortunately did not lend themselves to transformations into useful dyes. We therefore regretfully abandoned this attractive class of compounds and went on to other work. Now, these benzoheptoxdiazines seemed to be rather well-suited as starting materials for a broad synthetic program aimed at the synthesis of biologically active products. [...] These compounds fulfilled all the criteria which seemed important to us...We therefore planned to prepare a number of the readily accessible aminoketones as starting materials, convert them into oximes, and use various acids for the acylation to [various derivative compounds].[...] Our plan was the synthesis of new compounds which by treatment with amines, could be converted into products possessing basic side chains...The reaction products, we hoped might have interesting properties, since it is known that basic groups very often impart biological activity. In the midst of our synthetic studies, we began to have doubts about the structure of heptoxdiazines of [two other structures, not drawn]. Particularly, the results of hydrogenation experiments were quite unexpected and revealing. The oxygen was removed with great ease and the products, formed in good yield, were quinazolines. Additional studies showed beyond any doubt that the so-called heptoxdiazines...did not posess the postulated structure but were in fact quinazoline 3-oxides [...] At that time (this was the second half of 1955) other problems forced us to drastically curtail our synthetic work in the quinazoline field. Later, in April 1957, intensive experimental work involving degradative work and synthetic studies resulted finally in an almost complete stoppage of work. The laboratory benches were covered with dishes containing crystalline samples, and flasks and beakers with mothor liquors which were expected to yield crystalline products. The bench working area had shrunk to almost zero, and a major clean up operation was in order. Therefore, many old mothor liquors which had refused to yield crystalline products were discarded, crystalline products were collected, discarded if useless, or bottled, if interesting. During this operation, my coworker, Earl Reeder, drew my attention to a few hundred miiligrams of two products, a nicely crystalline base and its hydrochloride. The base had been prepared in 1955...by treatment of [a quinazoline with a Cl bound to the 6 carbon] with methylamine, and its hydrochloride in 1956. The products were not submitted for pharmacological testing at that time because of our involvement with other problems. Since the compounds were pure and had the expected composition, we submitted the water soluble salt for pharmacological evaluation, instead of discarding it. We thought that the expected negative pharmacological result would complete our work with this series of compounds and yield at least some publishable material. Little did we know that this was the start of a program which would keep us busy for many years. The product was submitted for testing in May 1957 and resulted, after a few days, in an enthusiastic telephone call from our pharmacologist, Dr. Lowell O. Randall. He informed us that the compound posessed unusually interesting properties in the tests which were generally used for preliminary screening of of tranquilizers and sedatives [...] The [results showed] that the new compound was much more effective than meprobamate in each of Dr. Randall's six preleiminary tests...The absence of direct hypnotic properties below the toxic dose was another interesting feature which differentiated it clearly from phenobarbital. It is also worth noting that it had no effect whatsoever on the autonomic nervous system, thereby differing characteristically from chlorpromazine and reserpine. The substance also had a pronounced taming effect on monkeys. The low toxicity (620 mg/kg p.o. in mice) was particularly encouraging and is, as was found later, typical for this group of compounds. While the compound underwent a whole gamut of sophisticated pharmacological tests by Dr. Randall and his staff, we in our laboratory were concerned with the chemistry of this unusual product. From the very beginning, we had reservations as to its structure, since the UV and IR spectra were completely different from the [quinazoline starting material] or those of other quinazoline 3-oxides. [...] The degradation products [found after treating with PCl3, hydrolysis of the product with acid], glycine and methylamine [and an aminobenzophenone] could result only from the hydrolysis of [a] benzodiazepine derivative and not from the quinazoline...or other conceiveable isomers. We were naturally greatly intrigued by this unusual transformation of a quinazoline 3-oxide into a benzodiazepine 4-oxide, and consequently studied various reaction conditions, temperatures, solvents, and the behavior of a number of analogs [etc...] [Once the reaction mechanisms and structure were worked out we filed] a patent application in 1958, claiming 2-amino-5-phenyl-1,4-benzodiazepine 4-oxides bearing various substituents on the amino group and in the benzo- and phenyl-rings. Because of the novelty of these products, the patent was granted within a year in July 1959 [...] Within a short time it became apparent that this compound possessed very desirable properties. The interest of the clinical investigators grew at such arate that within a relatively short time around 16,000 patients had been treated with this drug. These broad successful studies enabled us to file a New Drug Application within a very short time and to introduce the compound in 1960 under the trademark Librium(R). The generic name was originally methaminodiazepoxide but was later changed to chlordiazepoxide... ***** The story goes on to describe the development of diazepam (Valium), synthesized in 1959, approved in 1963, and all the other benzodiazpines. I hope this rather long-winded, copyright-violating, bandwidth-wasting post has at least set it in stone in doubters' minds that diazepam and other benzos are completely synthetic compounds, not derived from Valerian alkaloids/acids in any way shape or form. Stop the insanity. ==================================================================== From: nobody@REPLAY.COM (Anonymous) Subject: Re: valium (NOT DERIVED FROM VALERIAN!) Date: 1997/05/22 Newsgroups: alt.drugs.hard,alt.drugs.chemistry,alt.drugs,rec.drugs.misc MORE! The pharmacological actions of benzodiaepines and Valerian root extracts are also quite dissimilar. Benzodiazepines act by binding to a specific site on the GABA(A) receptor, increasing the receptor's affinity for the neurotransmitter. More GABA binds to the postsynaptic neuron, Cl- conductance is increased, and the firing threshold of the postsynaptic neuron is raised. Valerian root extracts, by contrast, appear to act presynaptically, either promoting the release of GABA from the presynaptic neuron or inhibting GABA breakdown. They have GABA-ergic properties in common, but this is a rather unremarkable fact, since nearly all sedative compounds (barbiturates, meprobamate, ethanol as well as anticonvulsant drugs) somehow facilitate the activity of GABA, a widely distributed inhibitory neurotransmitter. Here are some abstracts: Title Synaptosomal GABA release as influenced by valerian root extract--involvement of the GABA carrier. Author Santos MS; Ferreira F; Cunha AP; Carvalho AP; Ribeiro CF; Macedo T Source Arch Int Pharmacodyn Ther, 1994 Mar-Apr, 327:2, 220-31 Abstract The effect of an aqueous extract obtained from the roots of Valeriana officinalis was investigated on the uptake and release of GABA in synaptosomes isolated from rat brain cortex. Aqueous extract of valerian inhibited the uptake and stimulated the release of [3H]GABA, either in the absence or in the presence of K+ depolarization. The release was Na(+)-dependent and independent of the presence of Ca2+ in the external medium. It is concluded that valerian extract releases [3H]GABA by reversal of the GABA carrier, which is Na(+)-dependent and Ca(2+)-independent. This increase in [3H]GABA release appears to be independent from Na(+)-K(+)-ATPase activity and the membrane potential. Title [Biological activity of the sum of the valepotriates isolated from Valeriana alliariifolia] Author Dunaev VV; Trzhetsinskii SD; Tishkin VS; Fursa NS; Linenko VI Source Farmakol Toksikol, 1987 Nov-Dec, 50:6, 33-7 Abstract The native sum of valepotriates isolated from Val. alliariifolia Adams which was named valiracyl is an agent of low toxicity and exerts a pronounced neurotropic effect. Valiracyl suppresses the orientation reflex of animals in an "open field", decreases a spontaneous and caffeine-stimulated motor activity, potentiates and prolongs the action of barbiturates, significantly reduces aggressiveness of animals, decreases sensitivity to the convulsant effects of corasol and thiosemicarbazide, produces the antihypoxic and mild myorelaxant actions. The neurotropic effects of valiracyl are related to increased level of the GABA inhibition mediator and decreased intensity of bioenergetic processes in the brain. Title In vitro study on the interaction of Valeriana officinalis L. extracts and their amino acids on GABAA receptor in rat brain. Author Cavadas C; AraĈujo I; Cotrim MD; Amaral T; Cunha AP; Macedo T; Ribeiro CF Source Arzneimittelforschung, 1995 Jul, 45:7, 753-5 Abstract This work studied in vitro the interaction of aqueous and hydroalcoholic extracts of Valeriana officinalis L. and compounds that are present in the extracts (amino acids and valerenic acid) with the GABAA (gamma-aminobutyric acid) receptor, using the [3H] muscimol binding technique to crude synaptic membranes from rat brain cortices. Both extracts displaced [3H]muscimol bound and this effect is probably due only to their amino acid content, specially GABA. This fact explains the in vitro effect of valerian extracts on GABAA receptor but not their sedative effect.