Of 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. 

The relationship between 20 and reserpine (1) is close like reserpine, intermediate 20 possesses the linear chain of all five rings and all six stereocenters. With the exception of the 3,4,5-tri-methoxybenzoate grouping, 20 differs from reserpine (1) in one very important respect the orientation of the ring C methine hydrogen at C-3 in 20 with respect to the molecular plane is opposite to that found in reserpine. Intermediate 20 is a reserpate stereoisomer, epimeric at position 3, and its identity was secured by comparison of its infrared spectrum with that of a sample of (-)-methyl-O-acetyl-isoreserpate, a derivative of reserpine itself.9 Intermediate 20 is produced by the addition of hydride to the more accessible convex face of 19, and it rests comfortably in a conformation that allows all of the large groups attached to the D/E ring skeleton to be equatorially disposed. 

The Woodward total synthesis of reserpine is an inspirational accomplishment that will, no doubt, remain a classic in the history of total synthesis.10... 

VMATs are irreversibly inhibited by the potent antihypertensive drug reserpine. The depressive effects of reserpine helped to formulate the original monoamine hypothesis of affective disorders. Reseipine also appears to interact with the transporters near the site of substrate recognition. Tetrabenazine, which is used in treatment of movement disorders, inhibits VMAT2 much more potently than VMAT1, consistent with the less hypotensive action of this agent. 

By extraction of the roots of Rauwolfia serpentina (L.) Beuth. and column chromatographic separation of reserpine. 

Catecholamine Reserpine, propranolol, and other p blockers Placebo-controlled trial of reserpine had negative... 

Iproniazid also prevents the reserpine syndrome in rats. Reserpine blocks vesicular uptake of monoamines which, as a consequence, leak from the storage vesicles into the cytosol. Although these monoamines would normally be metabolised by MAO, they are conserved when a MAO inhibitor (MAOI) is present, and so co-administration of reserpine and a MAOI leads to accumulation of monoamines in the neuronal cytosol. It is now known that, when the concentration of cytoplasmic monoamines is increased in this way, they are exported to the synapse on membrane-bound monoamine transporters. The ensuing increase in monoamine transmission, despite the depletion of the vesicular pool, presumably accounts for the effects of iproniazid on the behaviour of reserpine-pretreated rats. 

Figure 4.60 Synthesis map showing starting materials used for the synthesis of reserpine.

Pearlman, B.A. (1979) A Total Synthesis of Reserpine. Journal of the American Chemical Society, 101, 6404-6408. 

Hanessian, S., Pan, J., CarneU, A., Bouchard, H., Lesage, L. (1997) Total Synthesis of (—)-Reserpine Using the Chiron Approach. Journal of Organic Chemistry, 62, 465-473. 

Mehta, G. Reddy, D.S. (2000) A Formal Synthesis of Reserpine Hydrindane Approach to the Woodward s Ring-E Precursor. Journal of the Chemical Society Perkin Transactions J, 1399-1404. 

Sparks, S.M., Gutierrez, A.J., Shea, K.f (2003) Preparation of Perhydroisoquinolines Via the Intramolecular Diels-Alder Reaction of N-3,5-Hexadienoyl Ethyl Acrylimidates A Formal Synthesis of ( )-Reserpine. Journal of Organic Chemistry, 68, 5274-5285. 

Wender, P.A., Schaus, J.M., White, A.M. (1987) General Methodology for cis-Hydroisoquinoline Synthesis. 3. A Sixteen Step Synthesis of Reserpine. Heterocycles, 25,263-270. 

But that was only one half of the logic behind the chemical-imbalance theory. The other half came from studies of reserpine, a drug that was extracted from Rauvolfia serpentina or the Indian snakeroot plant, which had historically been used to treat snakebite, hypertension, insomnia and insanity. In studies of animals, reserpine was reported to induce sedation and to decrease brain levels of norepinephrine, serotonin and dopamine. Clinical reports indicated that some people became severely depressed when taking reserpine.14 Putting these two findings together, it seemed likely that reserpine made people depressed because it decreased neurotransmitter levels. 

The re-examination of the clinical reports showing that most people who were given reserpine did not become depressed was not published until 1971, a few years after the chemical-imbalance theory had been popularized by Schildkraut and Coppen. But a decade before their influential articles were written, there had been a carefully controlled clinical trial on the effects of reserpine on mood.17 Far from confirming the belief that it made people depressed, the study seemed to show the reverse. Rather than making healthy people depressed, reserpine seemed to make depressed people better. As described by Michael Shepherd, the senior author of the study, in 1956 ... 

Masuoka, D.T., Alcaraz, A.R, and Schott, H.F., [3H]Dopamine release by d-amphetamine from striatal synaptosomes of reserpinized rats, Biochem. Pharmacol., 31, 1969, 1982. 

Costentin, J., Duterte-Boucher, D., Panissaud, C., and Michael-Titus, A. Dopamine D, and D2 receptors mediate opposite effects of apomorphine on the body temperature of reserpinized mice. Neuropharmacology. 29 31, 1990. 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

Dopamine depleting agents. Reserpine, a natural alkaloid that blocks vesicular transport of monoamines, depletes stored monoamines, including DA. DA depletion is associated with the emergence of parkinsonism. This effect of reserpine was among the first clues that PD is the result of DA deficiency (see above). Generally, the parkinsonism resulting from reserpine is reversible. 

Gainey, L.F., Jr. and J.R. Kenyon. 1990. The effects of reserpine on copper induced cardiac inhibition in Mytilus edulis. Comp. Biochem. Physiol. 95C 177-179. 

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