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Phenyltropane: Wikis


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Troparil: A structural analog of cocaine with omitted -COO- linkage – a parent compound of many MAT ligands (here in a unfavourable conformation of the O-Me. The methyl has to be at the other O, and trans)

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency.[1][2] In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these analogues. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

Contents

Uses

Addiction

The phenyltropane compounds were initially discovered by R. Clarke et al. during research to try and dissociate the stimulant properties of cocaine from its abuse and dependence liability.[3][4] The first simple phenyltropanes to be made (WIN 35065-2 and WIN 34,428) were shown to be active in behavioral assays only for the ββ-isomers. The activity of the corresponding αβ-isomers was disappointing.

It was later shown that WIN 35065-2 and WIN 34,428 are mostly dopamine selective reuptake inhibitors with some residual actions at the NET and SERT. This is in contrast to cocaine, which is a completely nonselective SNDRI. Given that other simple stimulant compounds such as amphetamines derive their mechanism of action through dopaminergic release, it would seem reasonable to presume that dopamine is the key neurotransmitter responsible for mediating the reinforcing (and hence addictive) actions of these drugs.[5]

The dopamine hypothesis.[6]

The role of the NET in mediating self-administration cannot be entirely ruled out.[7]

The relationship between the affinity of a psychostimulant for the SERT and its ability to evoke self-administration is negative.

Comparison of physical harm and dependence regarding various drugs (the British medical journal The Lancet).[8]

According to the graph, cocaine is ranked second only to heroin in terms of the physical harm that it does to the user. Given the high abuse and dependence liability that cocaine poses, it appears that there is an urgent need to develop substitute agonists that can help in curing this addiction. Agonist based therapies have been implemented successfully in the treatment of tobacco and heroin dependence, although no such medicine exists for the rehabilitation of stimulant abusers. It is true that SSRIs can reduce cocaine intake,[9] although this would be a poor strategy in human addicts due to the fact that it would probably result in poor patient compliance and high rates of relapse.

Animal studies on monkeys and rats have tried to assess the self administration propensity of phenyltropane analogs alongside cocaine. Frequently the analogs are administered prior to the start of a session to see if they can suppress cocaine lever responding. Most of the analogs behave in ways that might be considered typical for a DRI. In particular, they tend to stimulate locomotor activity, and cause nonselective reductions in cocaine intake relative to food.[10] At the dose that can reduce cocaine intake, most of the analogs require a high DAT occupancy.[11] This would mean that the agonists would need to be behaviorally active at the dose that can bring about reductions in cocaine craving. Most of the analogs will readily substitute for cocaine, although most do not elicit as many lever responses per session because of pharmacokinetic factors.[12] Since these agonists function as reinforcers, there is an obvious concern surrounding their abuse liability.

Nevertheless, a slow onset, long-duration agonist seems like a reasonable approach. Phenyltropanes are widely used in animal studies of drug addiction as they share the stimulant properties and reinforcing effects of cocaine, but with higher potency, less non-specific binding which avoids the cardiotoxicity associated with cocaine.[13]

RTI336.png

RTI-336 is an interesting example of a phenyltropane that is being explored in the context of a treatment for cocaine addiction.[14] RTI-336 is a DRI and thus specifically targets the DAT which is responsible for the addictive properties of cocaine. The above statement about the DAT is only true in so far as it has a magnified sense of importance in mediating the addictive properties, particularly of cocaine but also of psychostimulants in general. Nevertheless, in not wanting to oversimplify the situation too blindly, it needs to be addressed that the DAT is not the sole target of these drugs, in the case of reuptake inhibitors. It is obviously the case that dopamine is a biological precursor to noradenaline. DA is made from tyramine, which is made from tyrosine, which is a non-essential amino acid given that it can be made from phenylalanine.

Methamphetamine is more serotonergic than amphetamine. Perhaps there is a minor role for 5HT in psychostimulants that may be considered beneficial. However drugs that are too serotonergic may impact negatively on self-administration as demonstrated in animals under FR and PR schedules of reinforcement. In fact, the above was proven by Rothman for releasing agents under the PAL-287 program of related molecules. What was somewhat interesting is that although the reason for the lack of reinforcement of RTI-112 is now well established, closely related RTI-111 was able to behave in ways that might be typical for a nonselective SNDRI such as cocaine. The role of the NET is not completely deleterious. In a recent paper by Rothman on transporter substrates, he establishes that for releasers that are amphetamine-like, discrimination stimulus is more accurately dictated by NE release than DA release. Nobody is arguing against the importance of DA, but it must be conceded that catecholamine in general is important, although the exact ratio is 50:50 in the case of methylphenidate.

Weeding out SERT and NET affinity is desirable in the context that these molecular targets are less relevant to the goals of the treatment program, which is to reduce cocaine intake. It can be clearly seen that RTI-336 has fewer metabolically labile sites than cocaine, and therefore has a longer duration span.

Binding Ligands

These compounds are primarily used in scientific research, as their high binding affinity for monoamine transporters, and the wide range of radiolabelled phenyltropane compounds available with different binding specificities makes them very useful for mapping the distribution of the various monoamine transporters in the brain.

Other Uses

Some phenyltropane derivatives have also been researched for medical use in the treatment of conditions such as Parkinson's Disease[15] and Alzheimer's Disease, depression, and their strong appetite suppressant effects makes them promising candidates for facilitating weight loss in the treatment of obesity.

Structure-activity relationships

Transporter selectivity

Compounds are known with a pronounced selectivity for each MAT – dopamine[14], noradrenaline[16] and the serotonin transporter.[17]

Phenyltropane based "SNDRI's" are another possibility.[1][2] reuptake inhibition.

Related compounds

Closely related compounds have a varied aryl fragment, like naphthyl, or a varied tropane fragment like with exchanged heteroatom, trop-2-enes, quinuclidines, piperidines.

References

  1. ^ a b Carroll, F. (2003). "2002 Medicinal Chemistry Division Award address: monoamine transporters and opioid receptors. Targets for addiction therapy". Journal of medicinal chemistry 46 (10): 1775–1794. doi:10.1021/jm030092d. PMID 12723940.   edit
  2. ^ a b Runyon, SP; Carroll (2006). "Dopamine transporter ligands: recent developments and therapeutic potential". Current topics in medicinal chemistry 6 (17): 1825–43. doi:10.2174/156802606778249775. ISSN 1568-0266. PMID 17017960.   edit
  3. ^ CLARKE R; DAUM S. TROPANE-2-CARBOXYLATES AND DERIVATIVES. US 3813404; 1974-05-28.
  4. ^ Clarke, RL; Daum; Gambino; Aceto; Pearl; Levitt; Cumiskey; Bogado (1973). "Compounds affecting the central nervous system. 4. 3 Beta-phenyltropane-2-carboxylic esters and analogs". Journal of medicinal chemistry 16 (11): 1260–7. PMID 4747968.   edit
  5. ^ Ritz, MC; Kuhar (1993). "Psychostimulant drugs and a dopamine hypothesis regarding addiction: update on recent research". Biochemical Society symposium 59: 51–64. PMID 7910741.   edit
  6. ^ Zhu, J; Reith (2008). "Role of the dopamine transporter in the action of psychostimulants, nicotine, and other drugs of abuse". CNS & neurological disorders drug targets 7 (5): 393–409. doi:10.2174/187152708786927877. PMID 19128199.   edit
  7. ^ Cook, C.; Carroll, I.; Beardsley, P. (2001). "Cocaine-like discriminative stimulus effects of novel cocaine and 3-phenyltropane analogs in the rat". Psychopharmacology 159 (1): 58–63. doi:10.1007/s002130100891. PMID 11797070.   edit
  8. ^ Nutt D, King LA, Saulsbury W, Blakemore C (March 2007). "Development of a rational scale to assess the harm of drugs of potential misuse". Lancet 369 (9566): 1047–53. doi:10.1016/S0140-6736(07)60464-4. PMID 17382831.   edit
  9. ^ [1]Czoty, P.W., Ginsburg, B.C. and Howell, L.L. Serotonergic attenuation of the reinforcing and neurochemical effects of cocaine in squirrel monkeys. Journal of Pharmacology and Experimental Therapeutics, 300: 831-7, 2002.
  10. ^ Negus, S.; Mello, N.; Kimmel, H.; Howell, L.; Carroll, F. (2009). "Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys". Pharmacology, biochemistry, and behavior 91 (3): 333–338. doi:10.1016/j.pbb.2008.08.002. PMID 18755212.   edit
  11. ^ Howell, L.; Carroll, F.; Votaw, J.; Goodman, M.; Kimmel, H. (2007). "Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys". The Journal of pharmacology and experimental therapeutics 320 (2): 757–765. doi:10.1124/jpet.106.108324. PMID 17105829.   edit
  12. ^ Howell, L. (2008). "Nonhuman primate neuroimaging and cocaine medication development". Experimental and clinical psychopharmacology 16 (6): 446–457. doi:10.1037/a0014196. PMID 19086766.   edit
  13. ^ Phillips, K.; Luk, A.; Soor, G.; Abraham, J.; Leong, S.; Butany, J. (2009). "Cocaine cardiotoxicity: a review of the pathophysiology, pathology, and treatment options". American journal of cardiovascular drugs : drugs, devices, and other interventions 9 (3): 177–196. doi:10.2165/00129784-200909030-00005. PMID 19463023.   edit
  14. ^ a b Carroll, F.; Howard, J.; Howell, L.; Fox, B.; Kuhar, M. (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS journal 8 (1): E196–E203. doi:10.1208/aapsj080124. PMID 16584128.   edit
  15. ^ Madras, B. K.; Fahey, M. A.; Goulet, M.; Lin, Z.; Bendor, J.; Goodrich, C.; Meltzer, P. C.; Elmaleh, D. R. et al. (2006). "Dopamine transporter (DAT) inhibitors alleviate specific parkinsonian deficits in monkeys: association with DAT occupancy in vivo". The Journal of pharmacology and experimental therapeutics 319 (2): 570–585. doi:10.1124/jpet.106.105312. PMID 16885433.   edit
  16. ^ Carroll, F.; Tyagi, S.; Blough, B.; Kuhar, M.; Navarro, H. (2005). "Synthesis and monoamine transporter binding properties of 3alpha-(substituted phenyl)nortropane-2beta-carboxylic acid methyl esters. Norepinephrine transporter selective compounds". Journal of medicinal chemistry 48 (11): 3852–3857. doi:10.1021/jm058164j. PMID 15916437.   edit
  17. ^ Blough, B.; Abraham, P.; Lewin, A.; Kuhar, M.; Boja, J.; Carroll, F. (1996). "Synthesis and transporter binding properties of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters: serotonin transporter selective analogs". Journal of medicinal chemistry 39 (20): 4027–4035. doi:10.1021/jm960409s. PMID 8831768.   edit







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