Reserpine

Reserpine is a neuroleptic and an antihypertensive medication obtained from Rauwolfia 

Rauwolfia (Raudixin, Rauserpa, etc.), the powdered whole root of the Rauwolfia plant, is a tan, bitter, fine amorphous powder with a slight odor, sparingly soluble in alcohol and only very slightly soluble in water. 

Alseroxylon (Rauwiloid), an alkaloidal fraction from Rauwolfia root, is a reddish-brown amorphous powder with a characteristic odor. 

Deserpidine (Harmonyl) is an alkaloid from Rauwolfia root. 

Rescinnamine (Moderil) is an alkaloid of the alseroxylon fraction of Rauwolfia root. Syrosingopine (Singoserp) is a preparation made from reserpine by hydrolysis and 

The monoterpenoid-derived alkaloid reserpine (XLV, Fig. 3), the history and pharmacology of which have been the subjects of numerous reviews [251 to 254, 958-969], can be regarded as a structurally specific agent, both on account of the specific nature of its sedative action and because the bewildering complexity of its overall effects probably [969] resides simply in its ability to procure the release of monoamines from their storage sites, both central and peripheral - just as the complex actions of nicotine stem primarily from its action on the ganglia. The structurally specific nature of reserpine would also be borne 

The closely related alkaloids rescinnamine (XLV, R = 3,4,5-trimethoxy-cinnamyl Fig. 3) [982, 1030-1043] and deserpidine (11-desmethoxyreserpine) [982,1036-1039,1042,1044-1047] exhibit similar, though less potent, sedative and hypotensive properties to reserpine and they have seen clinical apphcation. In the synthetic compound methoserpidine the hypotensive properties are free from accompan5dng sedation provided only moderate doses are given [1048 to 1050], while the reserpic acid di-ester syrosingopine, exerts a mild h3 otensive effect with practically no accompanying sedation [1050-1057]. 

Chemical Name 1 l,17a-dimethoxy-18 -[(3,4,5-trimethoxybenzoyl)oxy] -3/3,20a-yohimban-16 -carboxylic acid methyl ester 

Trade Name Manufacturer Country Year Introduced 

Schwyzer, R. and Mueller, J. U.S. Patent 2533,771 May 6,1958 assigned to Ciba Pharmaceutical Products, Inc. 

16/3-carboxylic acid methyl ester Common Name 3,4,5-trimethoxybenzoyl methyl reserpate Structural Formula  

White prismatic crystals bitter in taste melts at 265°C (509°F) insoluble in water, moderately soluble in boiling alcohol, slightly soluble in chloroform and ether. 

The toxic effects from high doses of cinchonine include tinnitus, vomiting, diarrhea, and fever. The toxic effects noted in rats were 

Synonyms (3/l,16j6,17a, 18/l,20Q )-ll,17-di-methoxy-18-((3,4,5-trimethoxybenzoyl)-oxy)yohimban-16-carboxylic acid methyl ester 3,4,5-trimethoxybenzoyl methyl re-serpate austrapine sandril serpasil, ser-pine 

Reserpine occurs in the roots of Rauwolfia serpentina and other Rauwolfia species, such as R. micrantha, R. canescens, and R. vom-itoria Hook. It is used therapeutically as an antihypertensive agent and a tranquilizer. Its use has been reduced significantly because of toxic side effects. 

Crystalline prismatic solid decomposes at 264°C (507.2°F) weakly alkaline, pA 6.6 slightly soluble in water, dissolves readily in chloroform, glacial acetic acid, ethyl acetate, and benzene produces fluorescence solutions turn yellow on standing. 

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Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

Miscellaneous Pharmaceutical Processes. Solvent extraction is used for the preparation of many products that ate either isolated from naturally occurring materials or purified during synthesis. Among these are sulfa dmgs, methaqualone [72-44-6] phenobarbital [50-06-6] antihistamines, cortisone [53-06-5] estrogens and other hormones (qv), and reserpine [50-55-5] and alkaloids (qv). Common solvents for these appHcations are chloroform, isoamyl alcohol, diethyl ether, and methylene chloride. Distribution coefficient data for dmg species are important for the design of solvent extraction procedures. These can be determined with a laboratory continuous extraction system (AKUEVE) (244). 

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

A third study (85) enrolled 7825 hypertensive patients (55% males and 45% females) having diastoHc blood pressures (DBP) of 99—104 mm Hg (13—14 Pa) there were no placebo controls. Forty-six percent of the patients were assigned to SC antihypertensive dmg therapy, ie, step 1, chlorthaUdone step 2, reserpine [50-55-5] or methyldopa [555-30-6], and step 3, hydralazine [86-54-4]. Fifty-four percent of the patients were assigned to the usual care (UC) sources in the community. Significant reductions in DBP and in cardiovascular and noncardiovascular deaths were noted in both groups. In the SC group, deaths from ischemic heart disease increased 9%, and deaths from coronary heart disease (CHD) and acute myocardial infarctions were reduced 20 and 46%, respectively. 

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

In the post-World War II years, synthesis attained a different level of sophistication partly as a result of the confluence of five stimuli (1) the formulation of detailed electronic mechanisms for the fundamental organic reactions, (2) the introduction of conformational analysis of organic structures and transition states based on stereochemical principles, (3) the development of spectroscopic and other physical methods for structural analysis, (4) the use of chromatographic methods of analysis and separation, and (5) the discovery and application of new selective chemical reagents. As a result, the period 1945 to 1960 encompassed the synthesis of such complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward, R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork, 1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll (R. Woodward, 1960) (page 5). ... 

The indole alkaloids of the yohimbine-reserpine series exist in four configurations normal (74), alio (75), pseudo (76), and epiallo (77). The results of the mercuric acetate oxidation of the indole alkaloids are in general... 

Bohlmann et al. (118-121) observed that an infrared absorption band between 2700-2800 cm is characteristic of a piperidine derivative possessing at least two axial carbon-hydrogen bonds in antiperiplanar position to the free-electron pair on the nitrogen atom. The possibility of forming an enamine by dehydrogenation can be determined by this test. Compounds which do not fulfill this condition cannot usually be dehydrogenated (50, 122,123). Thus, for example, yohimbine can be dehydrogenated by mercuric acetate,whereas reserpine or pseudoyohimbine do not react (124). The quinolizidine (125) enamines (Scheme 4), l-azabicyclo(4,3,0)-nonane, l-azabicyclo(5,3,0)decane, l-azabicyclo(5,4,0)undecane, and l-azabicyclo(5,5,0)dodecane have been prepared in this manner (112,126). 

The indole ring system appears in many naturally-oeeuring substances including the amino acid tryptophan and the drug reserpine. 

A very interesting internal quaternization was discovered during the final proof of the configuration of reserpine. Attempted detos-... 

Acid-catalyzed C-3 epimerization of reserpine and other indolo[2,3-fl]quinolizi-dines 98H(48)1275. 

After filtering and evaporating the solvent under reduced pressure, the pasty residue, constituted by the enriched product, is diluted with 30 ml ether and in this way 0.225 g reserpine (which has not taken part in the reaction) is isolated by filtration. 

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