Reserpine functionality

Reserpine irreversibly inhibits the triphosphatase that maintains the proton gradient and so it depletes neurons of their vesicular store of transmitter. This explains why restoration of normal neuronal function rests on delivery of new vesicles from the cell bodies. Some amphetamine derivatives, including methylenedioxymethamphetamine (MDMA), are also substrates for the transporter and, as a result, competitively inhibit noradrenaline uptake. Another way of inhibiting the transporter is by dissipation of the pH gradient across the vesicular membrane i-chloroamphetamine is thought to act in this way. 

Gomez, A.M., L6pez, J.C., Fraser-Reid, B. (1994) Serial Radical Cyclization ofPyranose-Derived Dienes in the StereocontroUed Synthesis of Densely Functionalized Cyclohexanes. A Route to Woodward s Reserpine Precursor. Journal of Organic Chemistry, 59, 4048M 050. 

Mehta, G. Reddy, D.S. (1998) Reserpine Synthesis A Protocol for the Stereoselective Construction of the Densely Functionalized Ring-E. Journal of the Chemical Society Perkin Transactions I, 2125-2126. 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

Like the articles indicating that iproniazid and imipramine functioned as antidepressants, the conclusion that reserpine makes people depressed was based on clinical reports, rather than controlled trials. 

The answers are 321-cT 322-e, 323-i. (Hardman, pp 238-239, 791.) Reserpine is an adrenergic neuronal blocking agent that causes depletion of central and peripheral stores of NE and dopamine Reserpine acts by irreversibly inhibiting the magnesium-dependent ATP transport process that functions as a carrier for biogenic amines from the cytoplasm... 

Results and data gathered on mass spectroscopy of various indole alkaloids have been summarized by Hesse (320). The derivation of the characteristic fragments of indolo[2,3-a]quinolizidines has been interpreted by Gribble and Nelson (321), who investigated C-3, C-5, C-6, C-20, and C-21 deuterated derivatives of octahydroindolo[2,3-a]quinolizine (1). Kametani et al. have observed and proved, with labeled compounds, a methyl transfer from the ester function of reserpine derivatives to the basic nitrogen atom during mass-spectroscopic measurement (322). 

In addition to drugs administered specifically to produce a metabolic effect, there are drug-related physiological changes that cause laboratory test abnormalities. Many drugs have been associated with the appearance of abnormal liver function tests in a fashion that simulates extrahepatic obstruction. These drugs include, among others, chlorpromazine, cinco-phen, methyltestosterone, thiouracil, p-aminosalicylic acid, sulfadiazine, reserpine, meprobromate, novobiocin, caffeine, and phenacemide (L7, L8, S6). 

Peripheral nervous system side effects are the result of a reserpine-induced reduction of sympathetic function and unopposed parasympathetic activity symptoms include nasal congestion, postural hypotension, diarrhea, bradycardia, increased gastric secretion, and occasionally impotence. Because of the increased gastric secretion, reserpine is contraindicated for patients... 

Despite the documented efficacy and safety of the psychostimulants, their mechanism of action is not fully understood. Stimulants affect central nervous system (CNS) dopamine (DA) and norepinephrine (NE) pathways crucial in frontal lobe function. The stimulants act by causing release of catecholamines from the DA axons and blocking their reuptake. Methylphenidate releases catecholamines from long-term stores, so its effects can be blocked by pretreatment with reserpine. Amphetamines, on the other hand, release catecholamines from recently formed storage granules near the surface of the presynaptic neuron, so their action is not blocked by reserpine. In addition, the stimulants bind to the DA transporter in striatum (see Figures 2.6 and 2.7) and block the reuptake of both DA and NE. This action reduces the rate that catecholamines are removed from the synapse back into the axon and leads... 

A potentially useful route to reserpine alkaloids has been suggested by the application of the amino-Claisen reaction (Scheme 52) to the indolyl-substituted isoquinuclidine (268). Treatment of (268) with methyl propiolate gave the intermediate zwitterion (269) which rapidly rearranged to (270). This latter compound has all the necessary functionality for further elaboration into the reserpine ring system (B-82MI20700). 

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 ... 

Reserpine, used as a folk medicine in India, was found to have antipsychotic properties at about the same time as CPZ. Both agents affected the dopaminergic system, albeit in different ways, but the functional results were similar (i.e., lowering dopamine activity). This phenomenon has continued to be an important factor in hypotheses about the mechanism of action of these drugs and for biological theories about the pathophysiology of psychotic disorders. 

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). 

An ingenious new method for the preparation of Woodward s intermediate (97) by Pearlman70 constitutes another formal synthesis of reserpine. The essence of this new approach is an adaptation of the de Mayo reaction which allows the introduction of vicinal aldehyde and acetic ester functions on to a double-bond (Scheme 13). An internal [2tt + 27r] photocyclization of the diene (98) gave the tetracyclic cyclobutane derivative (99), which was converted into the ester (100) by standard procedures. Methanolysis of the acetate function with concomitant retro-aldol fission completed the introduction of the vicinal aldehyde and acetic ester functions obvious manipulation then gave the desired intermediate (97). 

Molecular cloning has identified two closely related but distinct vesicular monoamine transporters, VMAT1 and VMAT2 (Liu et al., 1992 Erickson et al., 1992 Liu and Edwards, 1997). Sequence analysis predicts 12 transmembrane domains with N- and C-termini in the cytoplasm, and the proteins show no sequence similarity to plasma membrane monoamine transporters (Nguyen et al., 1983 Neal and Chater, 1987 Neyfakh et al., 1991). Rather, they show similarity to bacterial proteins involved in detoxification (Figure 2). These bacterial proteins all function as H+ exchangers, and several are even inhibited by the same drugs that inhibit VMATs (e.g., reserpine). 

Metzger RR, Brown JM, Sandoval V, Rau KS, Elwan MA, Miller GW, Hanson GR, Fleckenstein AE (2002) Inhibitory effect of reserpine on dopamine transporter function. Eur J Pharmacol 456 39 13. 

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