Reserpine pharmacology

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). 

When Schildkraut introduced the monoamine theory of depression, he admitted that there was little direct evidence for it. Instead, it was based on the supposed effectiveness of antidepressant medication and the mistaken belief that reserpine makes people depressed. Schildkraut acknowledged that Most of this evidence is indirect, deriving from pharmacological studies with drugs such as reserpine, amphetamine and the monoamine oxidase inhibitor antidepressants which produce affective changes. 21 A half-century has passed since his chemical-imbalance theory of depression was introduced, and the presumed effectiveness of antidepressants remains the primary evidence in its support. But as we have seen, the therapeutic effects of antidepressants are largely due to the placebo effect, and this pretty much knocks the legs out from under the biochemical theory. 

Reserpine, an alkaloid from the Rauwolfia plant, abolishes the vesicular storage of biogenic amines (NE, dopamine = DA, serotonin = 5-HT) by inhibiting an ATPase required for the vesicular amine pump. The amount of NE re-Liillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

It became known in the same year (1954) that the substance reserpine, derived from the Indian plant Rauxcolfia serpentina, had antipsychotic effects similar to those of chlorpromazine This finding was of interest for two reasons the molecular structure of reserpine has some similarity to that of serotonin and LSD and it was found that reserpine liberates serotonin from presynaptic stores in the CNS and thus produces a short-lived excess supply of functionally available serotonin at the synapse. In the context of a serotonin hypothesis of schizophrenia, it could be postulated that the antipsychotic effect of reserpine was due to its ability to liberate serotonin presynaptically and make it functionally available. However, despite its scientific appeal, the serotonin hypothesis of schizophrenia did not last long because it was in conflict with both psychopathological and pharmacological findings ... 

Paralleling these clinical developments were basic pharmacological studies, which noted that reserpine ( 5, 6, 7 and 8) and a-methyidopa produced depression in patients treated for hypertension ( 9,10 and 11). The fact that the MAOIs and TCAs functionally increased norepinephrine (NE) activity while reserpine lowered its activity led Schiidkraut (12) and Bunney and Davis (13) to independently formulate the NE hypothesis of depression. This same line of reasoning was also applied to serotonin (5-HT) (14, 15). 

The results with methylphenidate, however, are more impressive. Two of three studies found a significant effect and the third found improvement on the patients subjective evaluation. Although amphetamine and methylphenidate are similar in their pharmacology, they differ in some respects. Amphetamine releases dopamine from newly synthesized pools (a-methyl-p-tyrosine-sensitive pool) whereas methylphenidate releases dopamine from storage sites (reserpine-sensitive sites). This pharmacological difference could be related to the apparent greater efficacy of methylphenidate. 

Reserpine (1) with its remarkable pharmacological properties remains an attractive synthetic target. The first total synthesis of reserpine (1), by... 

The acid-catalysed epimerization reaction often contributes to the change of conformation that alters the sterical shape of a compound. This may have a severe effect on pharmacological properties as with reserpine (1) and isoreserpine (2). The same seems to apply to the C-3 epimers yohimbine (78) and pseudoyohimbine (79). Yohimbine (78) blocks ai-receptors, whereas pseudoyohimbine (79) has little affinity for this... 

Takagi, H., Yamamoto, S., Takaori, S., and Ogui, K. "The Effect of LSD and Reserpine on the Central Nervous System of the CatJapanese Journal of Pharmacology 7,119-34, 958. 

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