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Encyclopedia > Nocaine
Nocaine
Systematic (IUPAC) name
(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate methyl ester
Identifiers
CAS number  ?
ATC code  ?
PubChem  ?
Chemical data
Formula C14H18ClNO2 
Mol. mass 267.76 g/mol
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.

? IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. ... CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences, mixtures and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... PubChem is a database of chemical molecules. ... A chemical formula (also called molecular formula) is a concise way of expressing information about the atoms that constitute a particular chemical compound. ... General Name, Symbol, Number carbon, C, 6 Chemical series nonmetals Group, Period, Block 14, 2, p Appearance black (graphite) colorless (diamond) Standard atomic weight 12. ... General Name, Symbol, Number hydrogen, H, 1 Chemical series nonmetals Group, Period, Block 1, 1, s Appearance colorless Atomic mass 1. ... General Name, Symbol, Number chlorine, Cl, 17 Chemical series halogens Group, Period, Block 17, 3, p Appearance yellowish green Standard atomic weight 35. ... General Name, Symbol, Number nitrogen, N, 7 Chemical series nonmetals Group, Period, Block 15, 2, p Appearance colorless gas Standard atomic weight 14. ... General Name, Symbol, Number oxygen, O, 8 Chemical series nonmetals, chalcogens Group, Period, Block 16, 2, p Appearance colorless (gas) very pale blue (liquid) Standard atomic weight 15. ... The molecular mass (abbreviated MM) of a substance, formerly also called molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of medication that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. ... It has been suggested that Effective half-life be merged into this article or section. ... Excretion is the process of eliminating waste products of metabolism and other materials that are of no use. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. ...

Legal status
Routes  ?

The Nocaine family includes a diverse assortment of piperidine based cocaine mimics. The parent compound Nocaine was developed in an attempt to develop a substitute drug for cocaine for the treatment of addiction; this is a significant field of research with much work ongoing, and dozens of novel compounds have been developed although none have yet come to market. The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ... Cocaine (see also: crack) is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. ...


Nocaine itself is also known as (+)-CPCA or 3α-carbomethoxy-4β-(4-chlorophenyl)-N-methylpiperidine, and was developed in the early 2000s, but since this time a large number of substituted phenylpiperidine derivatives have been discovered, hybridizing the basic nocaine structure with that of other similar molecules such as methylphenidate, meperidine and modafinil to create a large family of derivatives with a range of activity profiles and potential applications. In chemistry, the phenyl group or phenyl ring (often abbreviated as -Ph) is the functional group with the formula -C6H5 Picture where the six carbon atoms are arranged in a cyclic manner. ... R-phrases , , S-phrases , , , , Flash point 16 °C RTECS number TM3500000 Related compounds Related compounds pyridine pyrrolidine piperazine Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references Piperidine is an organic compound with the molecular formula C5H11N... Methylphenidate (MPH) is an amphetamine-like prescription stimulant commonly used to treat Attention-deficit hyperactivity disorder (ADHD) in children and adults. ... Pethidine (INN) or meperidine (USAN) (also referred to as: isonipecaine; lidol; operidine; pethanol; piridosal; Algil®; Alodan®; Centralgin®; Demerol®; Dispadol®; Dolantin®; Dolestine®; Dolosal®; Dolsin®; Mefedina®) is a fast-acting opioid analgesic drug. ... Modafinil (commercial trade names Provigil (US, UK, Italy), Vigil (Germany), Modalert (India), Modiodal (France, Mexico, Turkey), Modavigil (Australia), Alertec (Canada), and possibly Vigicer) is a eugeroic drug generally prescribed to treat narcolepsy, made by the pharmaceutical company Cephalon Inc. ...

Contents

Nocaine Pharmacology

Some JPET studies have been conducted on SS and (3R,4S) Nocaine, respectively.[1][2] Factors such as reinforcing ability and seizure thresholds were explored. Nocaine was found to produce some cocaine-like reinforcing effects, but not to the same extent as cocaine itself, leading to speculation that it might be suitable for a cocaine substitute for use in drug addiction treatment. At present however the main focus is on developing more potent and selective compounds derived from the basic nocaine structure.


The vinyl compound was picked to represent this series of compounds in LMA studies. Both cocaine and the vinyl compound stimulated LMA. However, cocaine is ~2.5 x more potent in increasing the distance traveled. In contrast, the vinyl compound is about ~2.4 x more potent in enhancing stereotypic movements. Both cocaine and vinyl-Nocaine had a similar time-course on locomotor effects, which was ~2 h.


Modafinil Hybrids

A large number of derivatives of Nocaine were prepared that contain a highly functionalized thioalkyl chain at the 3 position. The side-chain of the wake-promoting agent modafinil was used as a punitive lead to fuel this compounds discovery.[3] Most of these ligands were more potent inhibitors at NET compared to DAT or SERT. However, in the case of the ligand depicted below, activity at all three MA systems was bordering on <1nM affinity.



The ligand with a -CH2-CH2-OH abridging the unoxidized sufur atom is somewhat NET selective, and potent; hence a SNERI or SNARI. These are quite rare relative to SDARIs and SSRIs and thus in high demand (J. Musachio),[4] although obviously not desipramine. It is no accident that the (3R,4S) isomer is the one eliciting the positive in vitro biassay test results (Rong He, Toru Kurome).[5] In fact NET inhibitors are demanded strongly enough that Jia Zhou was prepared to perform some extremely challenging chemistry in order to obtain some.[6] These are important probes but it should be emphasized that they are not thought to be strongly reinforcing and hence have limited abuse potential (Sunmee Wee, Zhixia Wang).[7] CoMFA contour maps provide a visual representation of prospective binding modes of the 3-substituent of the piperidine-based analogues of cocaine and can be used to design novel DAT inhibitors that may be useful for the treatment of cocaine abuse and certain neurological disorders (Hongbin Yuan).[8] Desipramine is a tricyclic antidepressant (TCA) that inhibits the reuptake of norepinephrine. ... Wiktionary has a definition of: In vitro In vitro (Latin: within glass) means within a test tube, or, more generally, outside a living organism or cell. ...


Methylphenidate Analogs

Inhibition of [125I]RTI-55 Binding (Ki, nM) and [3H]Monoamine Uptake (IC50, nM) by (±)-threo Methylphenidate Diastereoisomers.
Identification Marker DAT IC50, nM (Ki, nM) NET IC50, nM (Ki, nM) SERT IC50, nM (Ki, nM) IC50 and (Ki) Ratios
R X N [3H]Dopamine D.R. [3H]Noradrenaline D.R. [3H]Serotonin D.R. NE ÷ DA SER ÷ NE
Cocaine 240 ± 15 (500 ± 65) 0.48 210 ± 30 (500 ± 90) 0.42 250 ± 40 (340 ± 40) .7353 0.875 (1) 1.190 (0.68)
MeOC=O H H 79 ± 16 (110 ± 9) .7182 61 ± 14 (660 ± 50) .0924 51K ± 7K (65K ± 4K) .7846 .7722 (6) 836.1 (98.48)
O=COMe p-Cl H 11 ± 2 (25 ± 8) 0.44 11 ± 3 (110 ± 40) 0.1 6K ± 1h (>9.8K) 1.633 1 (4.4) 890.9 (54.55)
methyl p-Cl H 22 ± 7 (180 ± 70) .1222 35 ± 13 (360 ± 140) .9722 1.9K ± 3h (4.9K ± 5h) .3878 1.591 (2) 54.29 (13.61)
ethyl p-Cl H 23 ± 5 (37 ± 10) .6216 210 ± 30 (360 ± 60) .5833 2.4K ± 4h (7.8K ± 8h) .3077 9.130 (9.730) 11.43 (21.67)
1-propyl p-Cl H 7.4 ± 0.4 (11 ± 3) .6727 50 ± 15 (200 ± 80) 0.25 2.9K ± 11h (2.7K ± 6h) 1.074 6.757 (18.18) 58 (13.5)
iso-propyl p-Cl H 32 ± 6 (46 ± 16) .6957 51 ± 20 (810 ± 170) .0630 3.3K ± 4h (5.3K ± 13h) .6226 1.594 (17.61) 64.71 (6.54)
1-butyl p-Cl H 8.2 ± 2.1 (7.8 ± 1.1) 1.051 26 ± 7 (230 ± 30) .1130 4K ± 4h (4.3K ± 4h) .9302 3.171 (29.49) 153.8 (18.70)
iso-butyl p-Cl H 8.6 ± 2.9 (16 ± 4) .5375 120 ± 40 (840 ± 130) .1429 490 ± 80 (5.9K ± 9h) .0831 13.95 (52.5) 4.083 (7.024)
1-pentyl p-Cl H 45 ± 14 (23 ± 7) 1.957 49 ± 16 (160 ± 40) .3063 1.5K ± 3h (2.2K ± 1h) .6818 1.089 (6.957) 30.61 (13.75)
iso-pentyl p-Cl H 14 ± 2 (3.6 ± 1.2) 3.889 210 ± 40 (830 ± 110) .2530 7.3K ± 14h (5K ± 470) .1137 15 (230.6) 34.76 (6.024)
3-pentyl p-Cl H 240 ± 60 (400 ± 80) 0.6 330 ± 80 (970 ± 290) .3402 >9.4K (3.9K ± 3h) 2.410 1.375 (2.425) 28.48 (4.021)
c-pentyl p-Cl H 27 ± 8.3 (36 ± 10) 0.75 44 ± 18 (380 ± 120) .1158 4.6K ± 8h (5.7K ± 11h) .8070 1.630 (10.56) 104.5 (15)
neo-pentyl p-Cl H 60 ± 2 (120 ± 40) 0.5 520 ± 110 (140 ± 400) .3714 >8.3K (3.9K ± 5h) 2.128 8.667 (11.67) 15.96 (7.5)
c-pentymethyl p-Cl H 21 ± 1 (9.4 ± 1.5) 2.234 310 ± 40 (1.7K ± 310) .1824 2.1K ± 9h (2.9K ± 80) .8095 14.76 (180.9) 6.774 (1.706)
c-hexymethyl p-Cl H 230 ± 70 (130 ± 40) 1.769 940 ± 140 (4.2K ± 2h) .2238 1K ± 2h (900 ± 400) 1.111 4.087 (32.31) 1.064 (.2143)
benzyl p-Cl H 370 ± 90 (440 ± 110) .8409 2.9K ± 6h (2.9K ± 8h) 1 1.1K ± 2h (1.1K ± 2h) 1 7.838 (6.591) .3793 (.3793)
β-phenethyl p-Cl H 160 ± 20 (24 ± 9) 6.667 680 ± 240 (1.8K ± 6h) .3778 650 ± 210 (640 ± 60) 1.016 4.25 (75) .9559 (.3556)
γ-phenpropyl p-Cl H 290 ± 90 (440 ± 150) .6591 600 ± 140 (490 ± 100) 1.224 1.6K ± 3h (700 ± 200) .3063 2.069 (1.114) 2.667 (1.429)
iso-butyl m-Cl H 2.8 ± 0.4 (3.7 ± 1.1) .7568 14 ± 1 (23 ± 6) .6087 2.1K ± 1h (3.2K ± 4h) .6563 5 (6.216) 150 (139.1)

Recently, some new methylphenidate analogs have been prepared by Froimowitz et al.[9] In stark contrast to Nocaine, the RR isomer serves as the eutomer. An almost perfect computational overlap with the PT's was ample motivational driving force for conducting these studies. Methylphenidate (MPH) is an amphetamine-like prescription stimulant commonly used to treat Attention-deficit hyperactivity disorder (ADHD) in children and adults. ...


First Nocaine Triple Monoamine QSAR

Based upon the results reported in the tropane series, it became desirable to manipulate the weak phenyl-arecoline nucleus in ways that that would improve SERT affinity, and also strengthen DAT binding (Amir Tamiz, Jianrong Zhang).[10] A series of Nocaine analogs were tested at the three common monoamine transporters for their ability to inhibit the reuptake of radiolabelled tritium neurotransmitters, respectively. The uptake data and selectivity profiles of these compounds are listed in the table. The 3-(2-naphthyl) 2-CO2Me compound is actually a piperidine based analog of RTI-318. The p-allyl compound is a piperidine based mimic of RTI-301. It is depicted as the terminal alkene, although it should be emphasized that the olefin will internalize to RTI-296 upon exposure to light. The p-vinyl compound is a piperidine mimic of RTI-351.

First Nocaine Triple Monoamine QSAR
Identification Marker SERT / DAT / NET IC50, nM (Ki, nM) IC50 ÷ Ki Uptake Ratio
Config X N [3H]Serotonin [3H]Dopamine [3H]Noradrenaline SER DA NE DA/5HT NA/SER NE/DA
SS p-Vinyl Me 155 ± 3.9 (138 ± 3.5) 144 ± 20 (131 ± 18) 204 ± 5.6 (175 ± 4.8) 1.123 1.099 1.166 0.9493 1.268 1.336
SS p-Ethyl Me 275 ± 39 (255 ± 37) >1800 (>1700) >1300 (>1100) 1.078 1.059 1.182 >6.667 >4.314 0.6471
SS p-Allyl Me 334 ± 48 (309 ± 44) >1000 (964 ± 100) >1200 (>1000) 1.081 >1.037 1.2 3.120 >3.236 1.037
SS p-Ethynyl Me 189 ± 37 (175 ± 34) 213 ± 30 (187 ± 26) 399 ± 12 (364 ± 9.2) 1.080 1.139 1.096 1.069 2.080 1.947
SS p-Phenyl Me 67 ± 4.5 (62 ± 4.1) 184 ± 30 (173 ± 26) 239 ± 42 (203 ± 36) 1.081 1.064 1.177 2.790 3.274 1.173
SS 2-Naphthyl Me 8.2 ± 0.3 (7.6 ± 0.2) 23 ± 1.0 (21 ± 0.9) n.d. (34 ± 0.8) 1.079 1.095 2.763 4.474 1.619
(3R,4S) 2-Naphthyl Me 46 ± 4.4 (42 ± 4.0) >1000 (947 ± 135) n.d. (241 ± 1.7) 1.095 >1.056 22.55 5.738 0.2545
RR 2-Naphthyl Me 209 ± 17 (192 ± 16) 94 ± 9.6 (87 ± 8.9) n.d. (27 ± 1.6) 1.089 1.080 0.4531 0.1406 0.3103
(3S,4R) 2-Naphthyl Me 13 ± 0.7 (12 ± 0.7) 293 ± 6.4 (271 ± 5.9) n.d. (38 ± 4.0) 1.083 1.081 22.58 3.167 0.140
(3S,4R) 2-Naphthyl H2Cl 3.9 ± 0.5 (3.5 ± 0.5) 97 ± 8.6 (90 ± 8.0) 34 ± 2.5 (30 ± 2.3) 1.114 1.078 1.133 25.71 8.571 0.3333
β± 1-Naphthyl Me 113 ± 4.3 (101 ± 3.8) 326 ± 1.2 (304 ± 1.1) 337 ± 37 (281 ± 30) 1.119 1.072 1.199 3.010 2.782 0.9243
All data are mean values ± range or SEM of 2–5 separate experiments each conducted with 6 drug concentrations in triplicate.

http://www.unmc.edu/Pharmacology/receptortutorial/competition/analysis_sample4.htm


Nocaine: Ester and Amine Modifications

A series of novel N- and 3α-modified Nocaine analogs were synthesized and tested for their SNDRI activity.[11]


N-demethylation greatly favors SERT/NET affinity. In order to achieve this a small sacrifice in DAT affinity is the required toll, but this is a very modest charge considering the payback. The in vitro demethylation results displayed in the table are in solid agreement with the PT's.

Nocaine: N-demethylation and Ester Reduction QSAR
Configuration R N [3H]DA Ki(nM) [3H]SER Ki(nM) [3H]NE Ki(nM)
(3R,4S) MeOC=O Me 233 ± 62 8490 ± 1430 252 ± 43
(3R,4S) HOCH2 Me 497 ± 58 1550 ± 360 198 ± 53
(3R,4S) O=COMe H 279 ± 98 434 ± 50 7.9 ± 3.0
(3R,4S) H2COH H 836 ± 35 239 ± 28 69 ± 6

Nocaine-CH2OH is a very respectable 2 x weaker than Nocaine at the DA transporter. Moreover, Nocaine-CH2OH possesses 5.5 х stronger SERT affinity than Nocaine, whereas NET binding remains more or less constant.


LMA tests in mice and drug discrimination tests in rats were conducted. The behavioral effects of Nocaine was studied earlier, where it was shown to be a good stereo-enhancer but inferior to the PT's with regards to LMA. The lack of convulsion potential of Nocaine is valuable observation that should be reiterated.


Meperidine Analogs

In Vitro Data for Meperidine Analogs with Tritiated Radiotracers.
Tag DAT / SERT / Opioid (Ki, μM) and Dopamine (IC50, μM) Uptake Ratio
E Ar [3H]WIN 35,428 [3H]Paroxetine [3H]DAMGO [3H]Dopamine DAT/SERT μ/DAT μ/SERT
CO2Et Ph 17.8 ± 2.7 0.413 ± 0.044 0.92 12.6 ± 1.2 43.1 0.052 2.13
CN p-F 45 10.1 ± 0.4 15 8 nd nd nd
CN p-Cl 22.0 ± 10.1 5.11 ± 0.59 36.8 (51) 36 4.31 1.67 0.18
CN p-I 8.34 ± 0.67 0.430 ± 0.0034 17.3 (61) 36.7 ± 1.3 19.4 2.07 40.2
CN p-Me 41.8 ± 6.1 13.7 ± 0.4 40.6 (46) 22 3.05 0.97 2.96
CN m,p-Cl2 2.67 ± 0.24 0.805 ± 0.12 40.0 (46) 11.1 ± 1.2 3.32 15.0 49.7
CN β-Naph 2.36 ± 0.66 0.125 ± 0.022 15.4 (61) 21.8 ± 1.2 18.9 6.53 123
CO2Et p-F 10.7 ± 2.3 0.308 ± 0.026 1.47 47 34.7 0.14 4.77
CO2Et p-Cl 4.10 ± 1.27 0.277 ± 0.040 4.41 26.9 ± 1.2 14.8 1.08 15.9
CO2Et p-I 3.25 ± 0.20 0.0211 ± 0.0024 2.35 11.1 ± 1.2 155 0.72 111
CO2Et p-Me 12.4 ± 5.2 1.61 ± 0.11 2.67 76.2 ± 1.2 7.69 0.22 1.66
CO2Et m,p-Cl2 0.125 ± 0.015 0.0187 ± 0.0026 2.04 1.40 ± 1.25 6.68 16.3 109
CO2Et β-Naph 1.14 ± 0.38 0.0072 ± 0.0001 2.03 11.6 ± 1.3 158 1.78 282
All values are the mean ± SEM of three experiments performed in triplicate. Percent inhibition at highest dose tested (100μM).

Some analogs of meperidine were prepared, initially with a bias toward improving DAT binding, but it turned out that these analogs favor the SERT and can even be made selective for this transporter under optimum circumstances (Stacey Lomenzo, Sari Izenwasser).[12][13] The authors were keen to elucidate SERT ligands with improved DAT affinity, prompting them to venture into a project where modification of the -CO2Et was embarked on.[14] Unfotunately, none of the new analogs possessed the desired DAT improvement, although some other the new compounds were more SERT selective and also could be made metabolically more hardy. None of the analogs tested produced LMA effects or substituted for cocaine in drug discrimination studies. The authors hypothesized that opioid receptor involvement is accountable for the lack of LMA of these analogs. Pethidine (INN) or meperidine (USAN) (also referred to as: isonipecaine; lidol; operidine; pethanol; piridosal; Algil®; Alodan®; Centralgin®; Demerol®; Dispadol®; Dolantin®; Dolestine®; Dolosal®; Dolsin®; Mefedina®) is a fast-acting opioid analgesic drug. ...


Bivalent

A range of bivalent α-(4-chlorophenyl) arecoline compounds were prepared in enantiomerically pure form. The optimum chain length of the spacer for SERT activity was five carbons long. In the case of the (3S,4R) enantiomer this led to the creation of an SSRI that was approaching <1nM activity. A suitable explanation for this might be that the separation distance between the two molecules is just right to allow binding onto two adjacent receptors. The chain length and choice of enantiomer were altered to yield other active inhibitors with varying potencies and SERT/NET/DAT ratios.


Oxadiazoles

"The synthesis of novel 4β-aryl-1-methyl-3α-(3-substituted-1,2,4-oxadiazol-5-yl)piperidines, bioisosteres of ester (+)-1, is described. The synthesized oxadiazoles were evaluated for their affinity to the DAT and their ability to inhibit monoamine reuptake at the DAT, NET, and 5HTT. The results show that affinity to the DAT and ability to inhibit the reuptake at the DAT, NET, and 5HTT is a function of the size of the substituent in the oxadiazole ring. (+)-(3R,4S)-4β-(4-Chlorophenyl)-1-methyl-3α-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine [(+)-2a], which is structurally and pharmacologically most similar to the ester (+)-1 in this series, showed at least a 2-fold longer duration of action when compared to ester (+)-1."[15]


Human Embryonic Kidney (HEK)

"A series of 3-carbomethoxy-4-(aryl-substituted)piperidines with various aryl groups were synthesized and examined for binding and reuptake inhibition at the human dopamine transporter, the human serotonin transporter, and the human norepinephrine transporter. The binding potency and reuptake inhibition efficacy was compared with that of (−)-cocaine to determine the significance of removing the two-carbon bridge of the cocaine nucleus on the inhibition of transporter binding and reuptake. Of the transporters examined, the substituted piperidines were relatively selective for the human dopamine transporter. In all cases examined, the cis-diastereomer of the 3-carbomethoxy-4-(aryl-substituted)piperidine was observed to be a more potent inhibitor of the human dopamine transporter than the trans diastereomer. Based on the Ki (binding) and IC50 (reuptake inhibition) values obtained, the most potent inhibitor of the series was cis-3-carbomethoxy-4-(4′-chlorophenyl)piperidine, and this compound suppressed spontaneous- and cocaine-induced stimulation in non-habituated male Swiss-Webster mice. The conclusion is that substantial portions of the cocaine structure can be dissected away to provide compounds with significant binding and reuptake inhibition of the human dopamine transporter."[16]

Human Embryonic Kidney cells: Nocaine
Tag hDAT / hSERT / hNET IC50, nM (Ki, nM) D.R. IC50 ÷ Ki
Con. X Y HEK hDAT HEK hSERT HEK hNET hDAT hSERT hNET
β± Cl H 151 ± 6.88 (98.9 ± 6.42) 544 ± 208 (684 ± 205) 1841 ± 421 (2201 ± 545) 1.53 0.79 0.84
β± Me H 340 ± 55.9 (340 ± 26.1) 793 ± 75 (2248 ± 330.7) 724 ± 243 (2441 ± 141) 1.0 0.35 0.296
β± H H 4657 ± 2171 (5135±1463) 2198 ± 758 (>10uM) 1282 ± 262 (>10uM) 0.91 0.22 0.13
β± F H 1789 ± 581 (2665 ± 605) 3414 ± 591 (10uM) 4852 ± 1852 (10uM) 0.67 0.34 0.48
α± Cl H 325.2 ± 63.9 (356 ± 18.0) 3133 ± 67 (5223 ± 2127) 2084 ± 75 (2279 ± 843) 0.9 0.6 0.91
α± Me H 446.2 ± 126 (2038 ± 561) 2868 ± 931 (>10uM) 1127 ± 387 (>10uM) 0.22 0.29 0.11
α± H H >10uM (>10uM) 3891 ± 160 (>10uM) 2706 ± 894 (>10uM) 1.0 0.39 0.27
αβ± OMe H 4737 ± 2049 (4615 ± 894) 687 ± 57 (1287 ± 335.1) >10uM (>10uM) 1.03 0.83 1
αβ± H OMe >10uM (>10uM) 438 ± 225 (2518 ± 689) >10uM (>10uM) 1.0 0.17 1
αβ± F H 988 ± 465 (6831 ± 743.5) 3025 ± 313 (>10uM) >10uM (>10uM) 0.14 0.3 1

"When the IC50 value for neurotransporter reuptake inhibition is divided by the binding constant for inhibition of radiolabelled RTI-55 binding to provide a ratio this correlation ratio value can provide insight into the efficacy of a compound as an antagonist of cocaine action. An IC50/Ki correlation ratio of 25 or greater suggests that the compound possesses binding potency and reuptake inhibition efficacy of sufficient magnitude to compete with the pharmacological effects exerted by cocaine. However, none of the compounds examined attained the desired level of activity."


External links

Biochemistry is the study of the chemical processes and transformations in living organisms. ... Peptides (from the Greek πεπτος, digestible), are the family of short molecules formed from the linking, in a defined order, of various α-amino acids. ... Phenylalanine is one of the standard amino acids. ... A nucleic acid is a complex, high-molecular-weight biochemical macromolecule composed of nucleotide chains that convey genetic information. ... Lactose is a disaccharide found in milk. ... A polyunsaturated triglyceride. ... Many terpenes are derived from conifer resins, here a pine. ... The orange ring surrounding Grand Prismatic Spring is due to carotenoid molecules, produced by huge mats of algae and bacteria. ... Polypyrrole A Polypyrrole (PPy) is a chemical compound formed from a number of connected pyrrole ring structures. ... A cofactor is any substance that needs to be present in addition to an enzyme to catalyze a certain reaction. ... Steroid skeleton of lanosterol. ... Molecular structure of flavone The term flavonoid refers to a class of plant secondary metabolites based around a phenylbenzopyrone structure. ... Diagram of Ephedrine An alkaloid, strictly speaking, is a naturally-occurring amine produced by a plant,[1] but amines produced by animals and fungi are also called alkaloids. ... Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. ... A glycoside is a molecule where a sugar group is bonded through its anomeric carbon to a nonsugar group by either an oxygen or a nitrogen atom. ... Diagram of Ephedrine An alkaloid, strictly speaking, is a naturally-occurring amine produced by a plant,[1] but amines produced by animals and fungi are also called alkaloids. ... 5-MeO-DMT is a very powerful psychedelic tryptamine. ... Dimethyltryptamine (DMT), also known as N,N-dimethyltryptamine, (not to be confused with 5-MeO-DMT), is a psychedelic. ... Harmala alkaloids, also known as Telepathine and Banisterine, are a group of naturally occurring beta-carboline alkaloids including harmine and harmaline. ... Psilocin, sometimes misspelled psilocine or psilotsin, is a psychedelic (hallucinogenic) mushroom alkaloid. ... Psilocybin (also known as psilocybine), is a psychedelic alkaloid of the tryptamine family. ... Reserpine is an indole alkaloid antipsychotic and antihypertensive drug known to irreversibly bind to storage vesicles of neurotransmitters such as dopamine, norepinephrine, and serotonin. ... Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. ... Tryptamine (3-(2-aminoethyl)indole) is a monoamine compound that is widespread in nature. ... Yohimbine, also known under the outdated names quebrachin, aphrodin, corynine, yohimvetol and hydroergotocin, is the principal alkaloid of the bark of the West-African tree Pausinystalia yohimbe Pierre (formerly Corynanthe yohimbe), family Rubiaceae (Madder family). ... Ephedrine (EPH) is a sympathomimetic amine similar in structure to the synthetic derivatives amphetamine and methamphetamine. ... This article does not adequately cite its references or sources. ... Phenethylamine, or β-Phenylethylamine, is an alkaloid and monoamine. ... Tyramine (4-hydroxy-phenethylamine) is a monoamine compound derived from the amino acid tyrosine. ... Caffeine is a xanthine alkaloid compound that acts as a stimulant in humans. ... Theobromine, also known as xantheose,[1] is a bitter alkaloid of the cacao plant. ... Theophylline is a methylxanthine drug used in therapy for respiratory diseases such as COPD or asthma under a variety of brand names. ... Coniine or 2-propylpiperidine is a poisonous alkaloid found in poison hemlock. ... Not to be confused with Niacin, which is the oxide of Nicotine, and has a very different biological effect. ... Quinine is a natural white crystalline alkaloid having antipyretic, anti-malarial with analgesic and anti-inflammatory properties and a bitter taste. ... Codeine (INN) or methylmorphine is an opiate used for its analgesic, antitussive and antidiarrheal properties. ... This article does not adequately cite its references or sources. ... Cocaine (see also: crack) is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. ... Structure of Aconitine Aconitine is a highly poisonous alkaloid derived from the aconite plant. ... Solanine is a glycoalkaloid poison found in species of the nightshade family. ... // Choline is a nutrient, essential for cardiovascular and brain function, and for cellular membrane composition and repair. ... Muscarine, L-(+)-muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species. ...

Patents

Clarke Patent[17] Kozikowski Patents[18][19][20][21][22][23]


Neurosearch

The present invention relates to novel piperidine-derivatives which are valuable monoamine neurotransmitter, i.e dopamine, serotonin and noradrenaline, re-uptake inhibitors and the use of the novel piperidine derivatives for the treatment of disorders or diseases responsive to the inhibition of monoamine neurotransmitter re-uptake, including diseases such as Parkinson's disease, depression, obsessive compulsive disorders, panic disorders, dementia, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety, eating disorders and drug addiction or misuse, including cocaine abuse.[24]


This invention relates to novel piperidine derivatives useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.[25]


References

  1. ^ [1]J. Pharmacol. Exp. Ther. 2003 305: 143-150. Nocaine
  2. ^ [2]J. Pharmacol. Exp. Ther. 2002 303: 211-217.
  3. ^ [3]J. Med. Chem.; (Letter); 2004; 47(24); 5821-5824. Zhou, J.; He, R.; Johnson, K. M.; Ye, Y.; Kozikowski, A. P.
  4. ^ [4] John L. Musachioa, Jinsoo Honga, Masanori Ichisea, Nicholas Senecaa, Amira K. Browna, Jeih-San Liowa, Christer Halldinb, Robert B. Innisa, Victor W. Pikea, Rong Hec, Jia Zhoud and Alan P. Kozikowski, Bioorganic & Medicinal Chemistry Letters Volume 16, Issue 12, 15 June 2006, Pages 3101-3104
  5. ^ [5]He, R.; Kurome, T.; Giberson, K. M.; Johnson, K. M.; Kozikowski, A. P. J. Med. Chem.; (Article); 2005; 48(25); 7970-7979.
  6. ^ [6]Drugs Future. 2004 December; 29(12): 1235–1244. Norepinephrine transporter inhibitors and their therapeutic potential.
  7. ^ [7]Drug and Alcohol Dependence Volume 82, Issue 2, 28 April 2006, Pages 151-157
  8. ^ [8]Yuan, H.; Kozikowski, A. P.; Petukhov, P. A. J. Med. Chem.; (Article); 2004; 47(25); 6137-6143.
  9. ^ [9]Froimowitz, M.; Gu, Y.; Dakin, L. A.; Nagafuji, P. M.; Kelley, C. J.; Parrish, D.; Deschamps, J. R.; Janowsky, A. J. Med. Chem.; (Article); 2007; 50(2); 219-232.
  10. ^ [10]Amir P. Tamiz, Jianrong Zhang, Judith L. Flippen-Anderson, Mei Zhang, Kenneth M. Johnson, Olivier Deschaux, Srihari Tella, and Alan P. Kozikowski. J. Med. Chem.; 2000; 43(6) pp 1215 - 1222
  11. ^ [11]Pavel A. Petukhov, Jianrong Zhang, Alan P. Kozikowski, Cheng Z. Wang, Yan Ping Ye, Kenneth M. Johnson, and Srihari R. Tella J. Med. Chem.; 2002; 45(15) pp 3161 - 3170
  12. ^ [12]Bioorganic & Medicinal Chemistry Letters, Volume 9, Issue 23, 6 December 1999, Pages 3273-3276 Stacey A. Lomenzo, Sari Izenwasser, Robert M. Gerdes, Jonathan L. Katz, Theresa Kopajtic and Mark L. Trudell
  13. ^ [13]Lomenzo, S. A.; Rhoden, J. B.; Izenwasser, S.; Wade, D.; Kopajtic, T.; Katz, J. L.; Trudell, M. L. J. Med. Chem.; (Article); 2005; 48(5); 1336-1343.
  14. ^ [14]Bioorganic & Medicinal Chemistry Volume 13, Issue 19, 1 October 2005, Pages 5623-5634
  15. ^ [15]Bioorganic & Medicinal Chemistry Letters Volume 11, Issue 16, 20 August 2001, Pages 2079-2083 Petukhov, Zhang, Johnson, Tella, Kozikowski
  16. ^ [16]X. Feng et al. Bioorganic & Medicinal Chemistry Volume 11, Issue 5 , 6 March 2003, Pages 775-780
  17. ^ United States Patent 3,813,404 Issue Date: May 28, 1974
  18. ^ Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6180648, 2001.
  19. ^ Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6472422, 2002.
  20. ^ Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6806281, 2004.
  21. ^ Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, WO9845263, 1998
  22. ^ Kozikowski; Alan P.; Araldi; Gian Luca; Tamiz; Amir P., WO0020390, 2000.
  23. ^ KOZIKOWSKI ALAN P (US); ZHOU JIA (US), WO2005041875, 2005.
  24. ^ United States Patent 6,376,673 Moldt, et al.
  25. ^ WO2004039778 Date: 2004-05-13 Inventor: WAETJEN FRANK (DK) Applicant: NEUROSEARCH AS (DK); WAETJEN FRANK (DK)

 
 

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