(+)-CPCA (nocaine, 3α-carbomethoxy-4β-(4-chlorophenyl)-N-methylpiperidine aka CTDP 31,446 ) is a stimulant drug similar in structure to pethidine (an opioid that possesses NDRI actions) and to RTI-31, but nocaine is lacking the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.
Since this time many 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. 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 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, and was found to substitute for cocaine in animal models while having significantly less abuse potential itself.
Background
Although Kozikowski reported compound with chlorine in 1998, plain phenyl was reported earlier than this by Plati.
Although novel ways to produce these compound exist, background stems from arecoline chemistry. E.g. paroxetine (Paxil) and femoxetine also from this arena of CNS chemicals. These serotonin based antidepressants, in case of Paxil N-normethyl also some acetylcholinergic according to texts.
Further nocaine derivatives was developed for treating addiction from Kozikowski's teachings: Smith specifically states that the butyrophenone analog of nocaine is an active agent, as well as specifying pthalimide type alkylamino agents.
Further support lends a scale-up process that also relies on arecoline, which is toxic and already active pharmaceutical salt:
The Ketanserin analog devised by Peter Meltzer uses an altogether different methodology of synthesis: The same procedure was employed years earlier for GSK1360707F, and was known from before this from RTI diaryltropanes. Thus, these methods is now well known in the art and does not necessarily rely on the use of arecoline as a starting material.
The Warner-Lambert Butler synthesis for example uses a 4-phenylnicotinic acid starting material: citing:
3',4'-Dichloro Advocacy
Thue method of improving the cited Ki by 3',4'-dichlorophenyl is now well known in the art and is heavily patented. piperidine-brasofensine piperidine-tesofensine Ritalin, Meperidine, sertraline indatraline dichloroisoprenaline sibutramine: mazindol dichloropane tramadol Amitifadine Diclofensine JNJ-7925476 venlafaxine
Pharmacology
Like cocaine, (–)-cis-CPCA and (+)-CPCA bind to the dopamine transporter and inhibit dopamine uptake, stimulate motor activity in rodents and completely substitute for cocaine in discrimination tests. Pretreatment with (–)-cis-CPCA or (+)-CPCA enhances the cocaine discriminative stimulus in rats. However, there are a number of differences; the locomotor stimulant effects of the piperidine derivatives are much less than those induced by cocaine, and pretreating mice with (–)-cis-CPCA or (+)-CPCA does not increase cocaine induced convulsions, and actually reduced cocaine induced locomotor stimulation. The (–)-cis-CPCA isomer has similar reinforcing effects to cocaine as shown by fixed-ratio self-administration tests in rats, but (+)-CPCA has a flat dose-response curve, and similarly while (–)-cis-CPCA and cocaine had nearly identical break points in a "punished responding" (?) self-administration test, (+)-CPCA had a lower break point than either of the other drugs.
The generally lower efficacy of (+)-CPCA in locomotor and methamphetamine discrimination tests could result from the differential selectivity of the two isomers for the DAT relative to the SERT. That is, if serotonin receptor activation is requisite for maximal efficacy, the difference SERT affinity between (–)-cis-CPCA and (+)-CPCA might play a contributory role in accounting for the differences in the observed pharmacology. Catecholamine selective drugs, like TMP (methylphenidate), are reported to possess decent abuse potential though, so it is not easy to gauge why (+)-CPCA does not entice a strong self-administration propensity.