Studies on some semi-synthetic piperine analogous as Central Nervous System Depressants

Master's Thesis, 2009

83 Pages, Grade: 1











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Natural product drug discovery describes the use of natural resources in the process of finding new drug compounds. Together with synthetic chemistry, they represent complementary strategies for lead identification in drug discovery.

For more than 50 year, natural products have served us well combating infectious bacteria and fungi. During the 20th century, microbial and plant secondary metabolites helped to double our life span, reduced pain and suffering, and revolutionized medicine. The increased development of resistance to older antibacterial, antifungal, antitumor drugs has been challenged by (1) newly discovered antibiotics (e.g. candins, epothilones); (2) new semi-synthetic versions of old antibiotics (e.g. ketolides, glycylcylines); (3) older underutilized antibiotics (e.g. teicoplainin) ; and (4) new derivatives of previous undeveloped narrow spectrum antibiotics (e.g. streptogramins). In addition, many antibiotics are used commercially, or are potentially useful in medicine for purposes other than their antimicrobial action. They are used as anti-tumour agents, enzyme inhibitors including powerful hypocholesterolemic agents, immunosuppressive agents, antimigraine agents, and so on. A number of these products were first discovered as antibiotics that failed in their development as such, or as mycotoxins.

It is unfortunate that the pharmaceutical industry has downgraded natural products 34just at the time that new assays are available and major improvements have been made in detection, characterization, and purification of small molecules. With the advent of combinatorial biosynthesis, thousands of new derivatives can now be made by a biological technique complementary to combinatorial chemistry. New methods are being developed to cultivate the so called unculturable microbes from the soil and the sea. High –throughput screening (HTS) of combinatorial chemicals has not provided the numbers of high- quality leads that were anticipated. It has virtually eliminated the most unique source of chemical diversity, i.e. natural products, from the playing field, in favour of combinatorial chemistry. Combinatorial chemistry mainly yields minor modifications of present day drugs and absolutely requires new scaffolds.

New Drug Application 1,5

Natural products have been an overwhelming success in our society. They have reduced pain and suffering, and revolutionized medicine by facilitating the transplantation of organs. Natural products are the most important anticancer and anti-infective agents. More than 60% of approved and pre new drug application (NDA) candidates are either natural products or related to them, not including biological such as vaccines and monoclonal antibodies.

Many natural products have reached the market without chemical modification, a testimony to the remarkable ability of microorganisms to produce small, drug like molecules. Indeed, the potential to commercialize a compound without chemical modification distinguishes products from all other sources of chemical diversity and fuels efforts to discover new compounds. Nature apparently optimizes certain compounds through many centuries of evolution. In these cases, production of the product directly by microbial fermentation is much more economical than using synthetic chemistry, e.g. , steroids, β- lactums, erythromycin. In these cases, the natural molecule was not used itself but served as a lead molecule for manipulation by chemical or genetic means, e.g. , cephaloporins, rifampicim. In these instances, the natural product presented important structural motifs and pharmacophores, which were then optimized via “semi-synthesis” to yield drugs with improved properties.

Methodologies In Natural Product Drug Discovery Process 1, 2,3

Early drug discovery involves several phases from target identification to preclinical development. The identification of small molecule modulators of protein function and the process of transforming these into high-content lead series are key activities in modern drug discovery. The Hit-to-Lead phase is usually the follow up of high-throughput screening (HTS).

Lead Compound 4

A lead compound (i.e. the "leading" compound, not lead metal) in drug discovery is a chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.

Lead compounds are often found in high-throughput screenings ("hits") or are secondary metabolites from natural sources.

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Figure 1: Drug Discovery Process. (Reproduced from [Last visited on 17.04.09] )

Hit confirmation

The Hit confirmation phase will be performed during several weeks as follows:

- Re-testing: compounds that were found active against the selected target are re-tested using the same assay conditions used during the HTS.
- Dose response curve generation: several compound concentrations are tested using the same assay, an IC50 or EC50 value is then generated
- Orthogonal testing: Confirmed hits are assayed using a different assay which is usually closer to the target physiological condition or using a different technology.
- Secondary screening: Confirmed hits are tested in a functional assay or in a cellular environment. Membrane permeability is usually a critical parameter.
- Chemical amenability: Medicinal chemists will evaluate compounds according to their synthesis feasibility and other parameters such as up-scaling or costs
- Intellectual Property evaluation: Hit compound structures are quickly checked in specialized databases to define patentability
- Biophysical testing: Nuclear magnetic resonance (NMR), Isothermal Titration Calorimetry, dynamic light scattering, surface plasmon resonance are commonly used to assess whether the compound binds effectively to the target, the stoïchiometry of binding and to identify promiscuous inhibitors.
- Hit ranking and clustering: Confirmed hit compounds are then ranked according to the various hit confirmation experiments.

Hit explosion

Following hit confirmation, several compound clusters will be chosen according to their characteristics in the previously defined tests. An Ideal compound cluster will:

- have compound members that exhibit a high afinity towards the target (less than 1 µM)
- show chemical tractability
- be free of Intellectual property
- not interfere with the P450 enzymes nor with the P-glycoproteins
- not bind to human serum albumin
- be soluble in water(above 100 µM)
- be stable
- have a good druglikeness
- exhibit cell membrane permeability
- show significant biological activity in a cellular assay
- not exhibit cytotoxicity
- not be metabolized rapidly
- show selectivity versus other related targets

Lead generation phase 4

The objective of this drug discovery phase is to synthesize lead compounds, new analogs with improved potency, reduced off-target activities, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics. This optimization is accomplished through empirical modification of the hit structure and/or by employing structure-based design if structural information about the target is available.

Importance of Plants in Drug Discovery4,5

Numerous methods have been utilized to acquire compounds for drug discovery, including isolation from plants and other natural sources, synthetic chemistry, combinatorial chemistry and molecular modeling.

Despite the recent interest in molecular modeling, combinatorial chemistry and other synthetic chemistry techniques by pharmaceutical companies and funding organizations, natural products and particularly medicinal plants, remain an important source of new drugs, new drug leads and new chemical entities (NCEs). According to Newman et al., 61% of the 877 small-molecule NCEs introduced as drugs worldwide during 1981–2002 was inspired by natural products.

These include: natural products (6%), natural products derivatives (27%), synthetic compounds with natural products-derived pharmacophore (5%) and synthetic compounds designed from natural products (natural products mimic, 23%).

Ten examples of successful drugs derived from plants are briefly described here.

- Arteether (1) is a potent anti-malarial drug and is derived from artemisinin, a sesquiterpene lactone isolated from Artemisia annua L. (Asteraceae), a plant used in traditional Chinese medicine.
- Galanthamine (2) is a natural product discovered through an ethnobotanical lead and first isolated from Galanthus woronowii Losinsk. (Amaryllidaceae) in Russia. Galanthamine is approved for the treatment of Alzheimer’s disease, slowing the process of neurological degeneration by inhibiting acetylcholine esterase as well as binding to and modulating the nicotinic acetylcholine receptor.
- Tiotropium (3) has been released recently in the US for treatment of chronic obstructive pulmonary disease. Tiotropium is an inhaled anticholinergic bronchodilator, based on ipratropium, a derivative of atropine, isolated from Atropa belladonna L. (Solanaceae) and other members of the Solanaceae family.
- Morphine- 6-glucuronide (4) is a metabolite of morphine from Papaver somniferum L. (Papaveraceae), reported as an alternative pain medication with fewer side effects than morphine.
- Exatecan (5) is an analogue of camptothecin isolated from Camptotheca acuminata Decne. (Nyssaceae) and being developed as an anticancer agent.
- Vinflunine (6) is a modification of vinblastine from Catharanthus roseus G. Don (Apocynaceae) for use as an anticancer agent with improved efficacy.
- Compounds (4–6) all are in phase III clinical trials. Thus, from these three examples, it is evident that modifications of existing natural products can lead to NCEs and possible drug leads, from medicinal plants.

- Calanolide A (7) is a dipyranocoumarin compound isolated from Calophyllum lanigerum var. Austrocoriaceum (Whitmore) P.F. Stevens (Clusiaceae), a Malaysian rainforest tree.

- The current emphasis of new drug discovery processes from plants is the development of products with new pharmacological modes of actions, apart from the known advantage of structural novelty. From India, three drugs qualify, i.e. flavopiridol (8), forskolin (9) and guggulsterone (10), on account of their modes of action.

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Figure 2: Chemical Structures of plant-derived drugs. . (Reproduced from S.M. Jachak and A. Saklani , Current Science, 2007, 92, 9 , 1251-1257)

Challenges in drug discovery from medicinal plants1,5

In spite of the success of drug discovery programmes from plants in the past 2–3 decades, future endeavours face many challenges. Natural products scientists and pharmaceutical industries will need to continuously improve the quality and quantity of compounds that enter the drug development phase to keep pace with other drug discovery efforts. The process of drug discovery has been estimated to take an average period of 10 years and cost more than 800 million dollars.

It is estimated that only one in 5000 lead compounds will successfully advance through clinical trials and be approved for use. In the drug discovery process, lead identification is the first step (Figure 2). Lead optimization (involving medicinal and combinatorial chemistry), lead development (including pharmacology, toxicology, pharmacokinetics, ADME and drug delivery), and clinical trials all take considerable time.

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Figure 3: Drug discovery process from plants (Reproduced from S. M. Jachak and A. Saklani , Current Science, 2007, 92, 9 , 1251-1257)


"Semisynthesis" or partial chemical synthesis is a type of chemical synthesis that uses compounds isolated from natural sources (e.g. plant material or bacterial or cell cultures) as starting materials. These natural biomolecules are usually large and complex molecules. This is opposed to a total synthesis where large molecules are synthesized from a stepwise combination of small and cheap (petrochemical) building blocks.Semisynthesis is usually used when the precursor molecule is too structurally complex, too costly or too inefficient to be produced by total synthesis. It is also possible that the semi-synthetic derivative outperforms the original biomolecule itself with respect to potency, stability or safety. Drugs derived from natural sources are usually produced by harvesting the natural source or through semi-synthetic methods: one example is the semisynthesis of LSD from ergotamine, which is isolated from ergot fungus cultures. The commercial production of paclitaxel is also based on semisynthesis (see: paclitaxel total synthesis). The antimalarial drug artemether (a component of Coartem) is a semi-synthetic derived from naturally occurring artemisinin. The latter is unstable due to the presence of a lactone group and therefore this group is replaced by an acetal through organic reduction with potassium borohydride and methoxylation .

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Inspired by this semi-synthetic pathway and keeping in mind the drug discovery from natural source, the plant Piper nigrum is selected for this thesis work. This plant is easily available and the main constituent piperine from this plant shows the Central Nervous System Depressant activity. So, further investigation can be done for the same pharmacological activity or other activity by semi-synthetic route from piperine. The semi-synthetic compound from piperine may be or may not be show the Central Nervous System Depressant activity. The semi-synthetic pathway is choosen as nature is a very good source drug . The natural compound will be easily available and there will be very less probability of toxicity. Further studies can be emphasized in this matter by synthesize analogues from the natural compound isolated from the plant.

Docking can be done for checking the probable activity of piperine and the other semi-synthetic piperine analogue on the selected receptor for pharmacological screening. For this, particular receptor and protein has been downloaded from the website And the receptor has been selected on the basis of the literature data of the piperine from different source. The particular receptor and the protein have been selected for docking for the piperine and the other ligand which will be synthesized from the piperine itself.


Central Nervous System Depressants 7

Depressants are psychoactive drugs which temporarily diminish the function or activity of a specific part of the body or mind . Examples of these kinds of effects may include anxiolysis, sedation, and hypotension. Due to their effects typically having a "down" quality to them, depressants are also occasionally referred to as "downers". Depressants are widely used throughout the world as prescription medicines and as illicit substances. When these are used, effects may include anxiolysis, analgesia, sedation, somnolence, cognitive/memory impairment, dissociation, muscle relaxation, lowered blood pressure/heart rate, respiratory depression, anesthesia, and anticonvulsant effects. Some are also capable of inducing feelings of euphoria. Depressants exert their effects through a number of different pharmacological mechanisms, the most prominent of which include facilitation of GBA and/or opioid activity, and inhibition of adrenergic, histamine and/or acetylcholine activity.

Depressants are used both individually and clinically for therapeutic purposes in the treatment of a number of indications, including the following:

- To reduce feelings of anxiety, panic, and stress.
- To induce sleepiness and relieve insomnia.
- To induce analgesia and relieve aches and pains.
- To reduce convulsions/seizures in the treatment of epilepsy .
- To cause muscle relaxation for those with muscle pain or spasms.
- To lower blood pressure and/or heart rate.
- To boost the mood and/or enhance sociability.

The major drug categories included in this classification are: alcohol, anesthetics, anti-anxiety medications, antihistamines, antipsychotics, hypnotics, narcotics, sedatives, and tranquilizers.

From the literature survey and the study of Piper nigrum and its main constituent piperine which is showing CNS Depressant activity i.e. Anticonvulsant , we came to know that this activity is due to the effect on some glutamate receptors. And, they are acting on the glutamate mediated Amino acid receptor. Piperine shows activity against the kainite dose. But, they are not showing any agonist or antagonist effect on Glutamate mediated Kainate Receptor . Now, researches show that piperine may be showing CNS depressing activity by acting on brain and neurones and has effect on conginitive behaviour. This is due to the effect on may be NMDA (N-methyl D-Aspartate) receptor or the other Glutamate receptor i.e., AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) receptor.

Detailed Description of Receptors8

Glutamate receptors are transmemebrane receptors located on neuron membranes. These receptors bind the neurotransmitter glutamate.

Glutamate is the most prominent nerutransmitter in the body, Being present in over 50% of nervous tissue . Glutamate was initially discovered to be a neurotransmitter following insect studies in the early 1960s. The primary glutamate receptor is specifically sensitive to N-Methyl-D-Aspartate (NMDA), which causes direct action of the central pore of the receptor, an ion channel, to drive the neuron to depolarize. Depolarization will trigger the firing, or action potential of the neuron,therefore NMDA is excitatory.

Types of glutamate receptors

There are two basic types of neural receptor: ionotropic, and metabotropic. There are many specific subtypes of glutamate receptors:

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Table 1: Glutamate receptor subtypes (Reproduced from [Last visited on 10.11.09 ] )

AMPA receptors9

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). Its name is derived from its ability to be activated by the artificial glutamate analog, AMPA. AMPARs are found in many parts of the brain and are the most commonly found receptor in the nervous system.

AMPA receptors are involved in mediating most forms of fast glutamatergic neurotransmission. There are four known subunits GluR1 to GluR4 - sometimes termed GluRA to GluRD - which are widely, but differentially, distributed throughout the CNS. The types of subunits forming these receptors determine their biophysical properties and pharmacological sensitivity. Two alternative splice variants of GluR1 to GluR4 subunits designated as ‘flip’ and ‘flop’ have been shown to differ in their expression throughout the brain and during development and to impart different pharmacological properties.

KAINATE receptors10

Other non-NMDA ionotropic receptor subunits are designated GluR5, GluR6, KA1 and KA2 and normally form receptor assemblies previously designated as high affinity kainate receptors. Kainate receptors were previously believed to be largely presynaptic, for example they are expressed in the dorsal root ganglia, and activation of these kainate receptors has been shown to facilitate transmitter release. LTP and short-term synaptic facilitation is reduced in knockout mice lacking the GluR6, but not the GluR5, kainate receptor subunit suggesting that kainate receptors act as presynaptic autoreceptors on mossy fibre terminals to facilitate synaptic transmission. More recent evidence indicates that they are also postsynaptically involved in neurotransmission in some pathways.


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Figure 4: Ampa and kainate receptors (Reproduced from [Last visited on 5.11.09])

NMDA receptors12

The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA (N -methyl D -aspartate) is a name of its selective specific agonist). Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations. This allows flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell.

Glutamate is in the glutamate binding site and glycine is in the glycine binding site. Allosteric sites that would cause inhibition of the receptor are not occupied. NMDARs require the binding of two molecules of glutamate or aspartate and two of glycine.

The Diversity Of Synaptic Plasticity13,14

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Figure6; Synapse-specific versus heterosynaptic potentiation in the basolateral amygdale. (Reproduced from [Last visited on 12.11.09 ])

Neurons in the basolateral amygdala apparently contain both NMDA receptors and GluR5-containing (calcium-permeable) kainate receptors, along with calcium-impermeable AMPA receptors. (a) Result of activating a synapse with an NMDA receptor and an AMPA receptor. Calcium entry through the NMDA receptor activates only local signals that affect AMPA and/or NMDA receptors, and possibly the presynaptic terminal through a retrograde messenger. The adjacent, inactive, receptor is not affected by these processes. (b) Result of activating a synapse with a GluR5-containing kainate receptor and an AMPA receptor.

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Figure 7: AMPA and NMDA receptor activation (Reproduced from [Last visited on 12.11.09] )

Modulation of AMPA receptor activity by associated proteins15

Excitatory synaptic plasticity in the brain is believed to underlie many aspects of learning and memory. This plasticity is in part the result of changes in both AMPA receptor number and activity at the synapse. AMPA receptors are ionotropic glutamate receptors present throughout the mammalian brain, which carry the bulk of normal fast synaptic transmission. GluR1 and GluR4 have long tails, while GluR2 and GluR3 have short tails. Specific regions within the C-terminal tails determine trafficking properties of the receptor complexes. In the hippocampus, subunit complexes containing GluR1 are inserted in response to activity, while complexes containing GluR2 are constitutively cycled into and out of the synaptic membrane.

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Figure 8: Modulation of AMPA Receptor Activity (Reproduced from [ Last visited on 11.11.09 ])


Piper nigrum. (Black pepper)16,17

Black pepper (Piper nigrum) is a flowering vine in the family Piperaceae, cultivated for its fruit, which is usually dried and used as a spice and seasoning. The fruit, known as a peppercorn when dried, is a small drupe five millimetres in diameter, dark red when fully mature, containing a single seed. Peppercorns, and the powdered pepper derived from grinding them, may be described as black pepper, white pepper, red/pink pepper, green pepper, and very often simply pepper. The terms pink peppercorns, red pepper, and green pepper are also used to describe the fruits of other, unrelated plants.

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Figure 9: Pepper plant with immature Figure 10: Pepper before ripening .


(Reproduced from [Last visited on 17.04.09] )

Black pepper is native to South India and is extensively cultivated there and elsewhere in tropical regions. Black pepper is also cultivated in the Coorg area of Karnataka.

Dried ground pepper is one of the most common spices in European cuisine and its descendants, having been known and prized since antiquity for both its flavour and its use as a medicine. The spiciness of black pepper is due to the chemical piperine. It may be found on nearly every dinner table in some parts of the world, often alongside table salt.

The word "pepper" is ultimately derived from the Sanskrit pippali, the word for long pepper via the Latin piper which was used by the Romans to refer both to pepper and long pepper, as the Romans erroneously believed that both of these spices were derived from the same plant. The English word for pepper is derived from the Old English pipor. The Latin word is also the source of German Pfeffer, French poivre, Dutch peper, and other similar forms. In the 16th century, pepper started referring to the unrelated New World chile peppers as well. "Pepper" was used in a figurative sense to mean "spirit" or "energy" at least as far back as the 1840s; in the early 20th century, this was shortened to pep.


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Figure 11: Black and white peppercorns

(Reproduced from [Last visited on 17.04.09])

Black pepper is produced from the still-green unripe berries of the pepper plant. The berries are cooked briefly in hot water, both to clean them and to prepare them for drying. The heat ruptures cell walls in the fruit, speeding the work of browning enzymes during drying. The berries are dried in the sun or by machine for several days, during which the fruit around the seed shrinks and darkens into a thin, wrinkled black layer. Once dried, the fruits are called black peppercorns.

White pepper consists of the seed only, with the skin of the fruit removed. This is usually accomplished by process known as retting, where fully ripe berries are soaked in water for about a week, during which the flesh of the fruit softens and decomposes. Rubbing then removes what remains of the fruit, and the naked seed is dried. Alternative processes are used for removing the outer fruit from the seed, including decortication, the removal of the outer layer from black pepper from berries through mechanical, chemical or biological methods.

In the U.S., white pepper is often used in dishes like light-coloured sauces or mashed potatoes, where ground black pepper would visibly stand out. There is disagreement regarding which is generally spicier. They have differing flavours due to the presence of certain compounds in the outer fruit layer of the berry that are not found in the seed.

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Figure 12: Black, green, pink (Schinus terebinthifolius), and white peppercorns.

(Reproduced from [Last visited on 17.04.09] )

Green pepper, like black, is made from the unripe berries. Dried green peppercorns are treated in a manner that retains the green colour, such as treatment with sulfur dioxide or freeze-drying. Pickled peppercorns, also green, are unripe berries preserved in brine or vinegar. Fresh, unpreserved green pepper berries, largely unknown in the West, are used in some Asian cuisines, particularly Thai cuisine. Their flavour has been described as piquant and fresh, with a bright aroma. They decay quickly if not dried or preserved.

A product called orange pepper or red pepper consists of ripe red pepper berries preserved in brine and vinegar. Ripe red peppercorns can also be dried using the same colour-preserving techniques used to produce green pepper. Pink pepper from Piper nigrum is distinct from the more-common dried "pink peppercorns", which are the fruits of a plant from a different family, the Peruvian pepper tree, Schinus molle, and its relative the Brazilian pepper tree, Schinus terebinthifolius. In years past there was debate as to the health safety of pink peppercorns, which is mostly no longer an issue. Sichuan peppercorn is another "pepper" that is botanically unrelated to black pepper.

Peppercorns are often categorised under a label describing their region or port of origin. Two well-known types come from India's Malabar Coast: Malabar pepper and Tellicherry pepper. Tellicherry is a higher-grade pepper, made from the largest, ripest 10% of berries from Malabar plants grown on Mount Tellicherry. Sarawak pepper is produced in the Malaysian portion of Borneo, and Lampong pepper on Indonesia's island of Sumatra. White Muntok pepper is another Indonesian product, from Bangka Island.

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Figure 13:-Pepper before ripening Figure 14:- High resolution picture

(Reproduced from [Last visited on 17.04.09] )

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Figure 15 :- Piper nigrum from an 1832 print

(Reproduced from [Last visited on 17.04.09] )

The pepper plant is a perennial woody vine growing to four metres in height on supporting trees, poles, or trellises. It is a spreading vine, rooting readily where trailing stems touch the ground. The leaves are alternate, entire, five to ten centimetres long and three to six centimetres broad. The flowers are small, produced on pendulous spikes four to eight centimetres long at the leaf nodes, the spikes lengthening to seven to 15 centimeters as the fruit matures. Black pepper is grown in soil that is neither too dry nor susceptible to flooding, moist, well-drained and rich in organic matter. The plants are propagated by cuttings about 40 to 50 centimetres long, tied up to neighbouring trees or climbing frames at distances of about twometres apart; trees with rough bark are favoured over those with smooth bark, as the pepper plants climb rough bark more readily. Competing plants are cleared away, leaving only sufficient trees to provide shade and permit free ventilation. The roots are covered in leaf mulch and manure, and the shoots are trimmed twice a year. On dry soils the young plants require watering every other day during the dry season for the first three years. The plants bear fruit from the fourth or fifth year, and typically continue to bear fruit for seven years. The cuttings are usually cultivars, selected both for yield and quality of fruit. A single stem will bear 20 to 30 fruiting spikes. The harvest begins as soon as one or two berries at the base of the spikes begin to turn red, and before the fruit is mature, but when full grown and still hard; if allowed to ripen, the berries lose pungency, and ultimately fall off and are lost. The spikes are collected and spread out to dry in the sun, then the peppercorns are stripped off the spikes.Black pepper is native to India. Within the genus Piper, it is most closely related to other Asian species such as Piper caninum .

Classification :

Piper nigrum L. 16,19

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Chemical Constituents:16-18

Peeper contains an alkaloid piperine (5-9%) , volatile oil (1-2.5%) , pungent resin (6.0%) , piperidine and starch (about 30%). The volatile oil which is yellowish in colour contains mainly l- phellandrene and caryophyllene.It has specific gravity of 0.898 – 0.9000 , optical rotation -3 to -5o , and refractive index of 1.4539-1.4977.

Active Constituent of Black Peeper: Piperine 19

Piperine is the alkaloid responsible for the pungency of black pepper along with chavicine (an isomer of piperine). It has also been used in some forms of traditional medicine and as an insecticide.

Piperine was first discovered by Hans Christian Ørsted in 1819. The pungency caused by capsaicin and piperine is caused by activation of the heat and acidity sensing TRPV ion channel TRPV1 on nociceptors (pain sensing nerve cells).

Piperine has also been found to inhibit human CYP3A4 and P-glycoprotein, enzymes important for the metabolism and transport of xenobiotics and metabolites. In animal studies, piperine also inhibited other enzymes important in drug metabolism. By inhibiting drug metabolism, piperine may increase the bioavailability of various compounds. Notably, piperine may enhance bioavailability of curcumin by 2000% in humans.

In February 2008 researchers discovered that piperine can stimulate pigmentation in the skin.






- Phytochemistry
- Journal of Natural Products
- Journal ofMedicinal Chemistry
- Journal of Combinatorial Chemistry
- Biomacromoleclues
- Journal of Ethnopharmacology
- Journal of Agricultural and Food Chemistry
- Journal of Industrial Engineering Chemistry
- Indian Journal of Chemistry
- Current Science
- Chemical Review
- Journal of Organic Chemistry
- Organic Letter
- European Journal Of Pharmaceutical Sciences
- The Journal Of Nutritional Biochemistry
- Food And Chemical Toxicology
- Biometals
- Achieves of Pharmaceutical Research
- Compendium of Indian medicinal plants ; volume 1 2.
- Encyclopedia of Indian medicinal plants
- Indian Material Medica; Volume 1
- Merck Index


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Studies on some semi-synthetic piperine analogous as Central Nervous System Depressants
Pharmaceutical Sciences
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Piperine, Piper nigrum, Semi-synthesis, Pharmacology, Pharmaceutical Sciences
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Dr. Manik Ghosh (Author)Dr. Barij Nayan Sinha (Author)Mushtari Akhter (Author), 2009, Studies on some semi-synthetic piperine analogous as Central Nervous System Depressants, Munich, GRIN Verlag,


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