Reserpine pharmacological effects

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). 

More interesting is the pharmacology of ajmaline (37), which is available in large quantities as a by-product of the reserpine extraction. Detailed pharmacological studies seemed to be more than justified because reserpine did not possess all the pharmacological effects of crude Rauwolfia extracts. Ajmaline was compared with quinidine and studied clinically in cardiac arrhythmias,... 

The pharmacological effects, on the nervous system, of reserpine, and of the hydrazines that inhibit monoamine oxidase (p. 360), are irreversible. These facts suggest that covalency is involved. 

In order to further examine this possibihty, amperometry and transmission electron microscopy (TEM) have been used simultaneously to directly determine if the l-DOPA and reserpine-mediated effects on qnantal release are accompanied by changes in vesicular volume [57], Pharmacological manipulations utilizing l-DOPA and reserpine directly affect the VMAT-mediated transport of catecholamines into PC12 vesicles [57], Electron microscopy has been used to measure changes in the size of vesicles not actively involved in exocytosis, and these measurements can be correlated with the amonnt of nenrotransmitter released using amperometry. 

MAOI counteract the pharmacological effects of drugs such as reserpine. They influence carbohydrate metabolism since blood lactate and pyruvate levels are increased. Most biochemical and pharmacological effects of MAOI. as measured by their intensity, onset, duration of action and nature, depend largely on the species, the tissue, the amine studied, the mode of administration and the drug pharmacokinetics, which make it almost impossible to predict accurately their action. 

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. 

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 ... 

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. 

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. 

Some preliminary pharmacological results have been obtained for 8,14-dihydronorsalutaridine and 8,14-dihydrosalutaridine (438). 8,14-Dihydronorsalutaridine has an antagonizing effect upon tetrabenazine which is a reserpine-like compound in its action on the central nervous system. 8,14-Dihydrosalutaridine (300 mg/kg) produces a moderate reduction of spontaneous motor activity in mice. 

Pharmacological evaluation of the ethers and their water-soluble salts revealed a marked sedative action in dogs without any demonstrable antihypertensive effect. The tranquilizing activity differs from that of reserpine in that its onset occurs within minutes rather than hours and the duration of action is considerably shorter than that of reserpine. Cumulation is not evident on repeated administration there is no effect on the gastrointestinal tract and no diarrhea occurs (182). Clinically, the normal, as well as the 18-epi, ethers were found to be effective when given to patients with mild or moderate anxiety. However, the tranquilizing activity of the normal ethers is considerably higher, and for all practical purposes the 18-epi ethers are not suitable for human therapy. 

Literature concerning model compounds is summarized in a recent publication (227), and subsequent papers by the same authors deal in greater detail with such work (228). From the material already presented in this chapter, it is obvious that structure-activity relationships in the reserpine field are still poorly understood, and so far the syntheses of model compounds, often prepared to test preconceived ideas, have not led to useful compounds. In the present state of our knowledge, it has been more profitable to discover substances whose clinical effects resemble reserpine as a result of careful pharmacological screening of... 

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