group, cid:44629033 (s/n/d = 11/14/190nm) ref: patent: trudell group: hk3-263 (s/n/d = 0.3/20/16nm): pfizer group cp-607366 & cp-939689. desmethylsertraline – active metabolite of sertraline; 76 nm for sert, 420 nm for net, 440 nm for dat 3,4-dichlorotametraline (trans-(1r,4s)-sertraline) (1980) venlafaxine analogues, lpm580098 & lpm580153. and tp1 later reassigned name to pa01. prc (carlier) group: prc200-ss (2008), prc050, and prc025. albany molecular research group (bruce molino) amr-2 (dat 3.1nm, sert 8.3nm, net 3.0nm): cid:49765424 (s)-enantiomer: : sk group: cid:44555333 & cid:49866033 boots uk: bts 74,398, spd-473 citrate: pridefine sme1ec2m3 sipi5357 (cid:52939791): 23j-s (s/n/d = 83/3.8/160nm): tetrazoles (rok): 10dl (cid:118713802) (s/n/d 7.6/45.2/330nm): 2at (cid:118706539): thiq derivatives: an12 (cid:10380161): patent: cid:9839278: 2j (cid:66572162) (s/n/d = 411/71/159nm): 6aq (cid:70676472) (s/n/d 44/10/32nm): naphthyl milnacipran analog (2007), cid:17748230 (s/n/d = 18/05/140nm). herbals the coca flour contains cocaine – natural alkaloid and drug of abuse ginkgo biloba extract (egb761) – "the norepinephrine (net), the serotonin (sert), the dopamine (dat) uptake transporters and mao activity are inhibited by egb761 in vitro" st john's wort – natural product and over-the-counter herbal antidepressant hyperforin adhyperforin uliginosin b – ic50 da = 90 nm, 5-ht = 252 nm, ne = 280 nm oregano extract. although not specifically a sndri, rosmarinus officinalis is one of the trimonoamine modulator (tmm) that affect ser/cas. hederagenin: toxicological toxicological screening is important to ensure safety of the drug molecules. in this regard, the p m-dichloro phenyl analog of venlafaxine was dropped from further development after its potential mutagenicity was called into question. the mutagenicity of this compound is still doubtful though. it was dropped for other reasons likely related to speed at which it could be released onto the market relative to the more developed compound venlafaxine. more recently, the carcinogenicity of prc200-ss was likewise reported. (+)-cpca ("nocaine") is the 3r,4s piperidine stereoisomer of (phenyltropane based) rti-31. it is non addictive, although this might be due to it being a ndri, not a sndri. the β-naphthyl analog of "nocaine" is a sndri though in the case of both the ss and rr enantiomers. consider the piperidine analogs of brasofensine and tesofensine. these were prepared by neurosearch (in denmark) by the chemists peter moldt (2002), and frank wätjen (2004–2009). there are four separate isomers to consider (ss, rr, s/r and r/s). this is because there are two chiral carbon sites of asymmetry (means 2 to the power of n isomers to consider where n is the number of chiral carbons). they are therefore a diastereo(iso)meric pair of racemers. with a racemic pair of diastereomers, there is still the question of syn (cis) or anti (trans). in the case of the phenyltropanes, although there are four chiral carbons, there are only eight possible isomers to consider. this is based on the fact that the compound is bicyclic and therefore does not adhere to the equation given above. it is complicated to explain which isomers are desired. for example, although alan p. kozikowski showed that r/s nocaine is less addictive than ss nocaine, studies on variously substituted phenyltropanes by f. ivy carroll et at. revealed that the ββ isomers were less likely to cause convulsions, tremor and death than the corresponding trans isomers (more specifically, what is meant is the 1r,2r,3s isomers). while it does still have to be conceded that rti-55 caused death at a dosage of 100 mg/kg, it's therapeutic index of safety is still much better than the corresponding trans isomers because it is more potent compound. in discussing cocaine and related compounds such as amphetamines, it is clear that these psychostimulants cause increased blood pressure, decreased appetite (and hence weight loss), increased locomotor activity (lma) etc. in the united states, cocaine overdose is one of the leading causes of er admissions each year due to drug overdose. people are at increased risk of heart attack and stroke and also present with an array of psychiatric symptoms including anxiety & paranoia etc. on removal of the 2c tropane bridge and on going from rti-31 to the simpler ss and rs nocaine it was seen that these compounds still possessed activity as ndris but were not powerful psychostimulants. hence, this might be viewed as a strategy for increasing the safety of the compounds and would also be preferable to use in patients who are not looking to achieve weight loss. in light of the above paragraph, another way of reducing the psychomotor stimulant and addictive qualities of phenyltropane stimulants is in picking one that is relatively serotonergic. this strategy was employed with success for rti-112. another thing that is important and should be mentioned is the risk for serotonin syndrome when incorporating the element of 5-ht transporter inhibition into a compound that is already fully active as a ndri (or vice versa). the reasons for serotonin syndrome are complicated and not fully understood. addiction drug addiction may be regarded as a disease of the brain reward system. this system, closely related to the system of emotional arousal, is located predominantly in the limbic structures of the brain. its existence was proved by demonstration of the "pleasure centers," that were discovered as the location from which electrical self-stimulation is readily evoked. the main neurotransmitter involved in the reward is dopamine, but other monoamines and acetylcholine may also participate. the anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum that project to the nucleus accumbens, amygdala, prefrontal cortex and other forebrain structures. there are several groups of substances that activate the reward system and they may produce addiction, which in humans is a chronic, recurrent disease, characterized by absolute dominance of drug-seeking behavior. according to various studies, the relative likelihood of rodents and non-human primates self-administering various psychostimulants that modulate monoaminergic neurotransmission is lessened as the dopaminergic compounds become more serotonergic. the above finding has been found for amphetamine and some of its variously substituted analogs including pal-287 etc. rti-112 is another good example of the compound becoming less likely to be self-administered by the test subject in the case of a dopaminergic compound that also has a marked affinity for the serotonin transporter. win 35428, rti-31, rti-51 and rti-55 were all compared and it was found that there was a negative correlation between the size of the halogen atom and the rate of self-administration (on moving across the series). rate of onset was held partly accountable for this, although increasing the potency of the compounds for the serotonin transporter also played a role. further evidence that 5-ht dampens the reinforcing actions of dopaminergic medications comes from the co-administration of psychostimulants with ssris, and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only. net blockade is unlikely to play a major role in mediating addictive behavior. this finding is based on the premise that desipramine is not self-administered, and also the fact that the nri atomoxetine was not reinforcing. however, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the pfc. relation to cocaine cocaine is a short-acting sndri that also exerts auxiliary pharmacological actions on other receptors. cocaine is a relatively "balanced" inhibitor, although facilitation of dopaminergic neurotransmission is what has been linked to the reinforcing and addictive effects. in addition, cocaine has some serious limitations in terms of its cardiotoxicity due to its local anesthetic activity. thousands of cocaine users are admitted to emergency units in the usa every year because of this; thus, development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health. many of the sndris currently being developed have varying degrees of similarity to cocaine in terms of their chemical structure. there has been speculation over whether the new sndris will have an abuse potential like cocaine does. however, for pharmacotherapeutical treatment of cocaine addiction it is advantageous if a substitute medication is at least weakly reinforcing because this can serve to retain addicts in treatment programmes: ... limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness. however, not all sndris are reliably self-administered by animals. examples include: prc200-ss was not reliably self-administered. rti-112 was not self-administered because at low doses the compound preferentially occupies the sert and not the dat. tesofensine was also not reliably self-administered by human stimulant addicts. the nocaine analog jzad-iv-22 only partly substituted for cocaine in animals, but produced none of the psychomotor activation of cocaine, which is a trait marker for stimulant addiction. legality cocaine is a controlled drug (class a in the uk; schedule ii in the usa); it has not been entirely outlawed in most countries, as despite having some "abuse potential" it is recognized that it does have medical uses. brasofensine was made "class a" in the uk under the mda (misuse of drugs act). the semi-synthetic procedure for making bf uses cocaine as the starting material. naphyrone first appeared in 2006 as one of quite a large number of analogs of pyrovalerone designed by the well-known medicinal chemist p. meltzer et al. when the designer drugs mephedrone and methylone became banned in the united kingdom, vendors of these chemicals needed to find a suitable replacement. mephedrone and methylone affect the same chemicals in the brain as a sndri, although they are thought to act as monoamine releasers and not act through the reuptake inhibitor mechanism of activity. a short time later, mephedrone and methylone were banned (which had become quite popular by the time they were illegalized), naphyrone appeared under the trade name nrg-1. nrg-1 was promptly illegalized, although it is not known if its use resulted in any hospitalizations or deaths. role of monoamine neurotransmitters monoamine hypothesis the original monoamine hypothesis postulates that depression is caused by a deficiency or imbalances in the monoamine neurotransmitters (5-ht, ne, and da). this has been the central topic of depression research for approximately the last 50 years; it has since evolved into the notion that depression arises through alterations in target neurons (specifically, the dendrites) in monoamine pathways. when reserpine (an alkaloid with uses in the treatment of hypertension and psychosis) was first introduced to the west from india in 1953, the drug was unexpectedly shown to produce depression-like symptoms. further testing was able to reveal that reserpine causes a depletion of monoamine concentrations in the brain. reserpine's effect on monoamine concentrations results from blockade of the vesicular monoamine transporter, leading to their increased catabolism by monoamine oxidase. however, not everyone has been convinced by claims that reserpine is depressogenic, some authors (david healy in particular) have even claimed that it is antidepressant. tetrabenazine, a similar agent to reserpine, which also depletes catecholamine stores, and to a lesser degree 5-ht, was shown to induce depression in many patients. iproniazid, an inhibitor of mao, was noted to elevate mood in depressed patients in the early 1950s, and soon thereafter was shown to lead to an increase in na and 5-ht. hertting et al. demonstrated that the first tca, imipramine, inhibited cellular uptake of na in peripheral tissues. moreover, both antidepressant agents were demonstrated to prevent reserpine-induced sedation. likewise, administration of dopa to laboratory animals was shown to reverse reserpine induced sedation; a finding reproduced in humans. amphetamine, which releases na from vesicles and prevents re-uptake was also used in the treatment of depression at the time with varying success. in 1965 schildkraut formulated the catecholamine theory of depression. this was subsequently the most widely cited article in the american journal of psychiatry. the theory stated that "some, if not all, depressions are associated with an absolute or relative deficiency of catecholamines, in particular noradrenaline (na), at functionally important adrenergic receptor sites in the brain. however, elation may be associated with an excess of such amines." shortly after schildkraut's catecholamine hypothesis was published, coppen proposed that 5-ht, rather than na, was the more important neurotransmitter in depression. this was based on similar evidence to that which produced the na theory as reserpine, imipramine, and iproniazid affect the 5-ht system, in addition to the noradrenergic system. it was also supported by work demonstrating that if catecholamine levels were depleted by up to 20% but 5-ht neurotransmission remained unaltered there was no sedation in animals. alongside this, the main observation promoting the 5-ht theory was that administration of a