However, by meta or para halogenation of the phenyl rings in the parent compound, we get a whole lot of crazy dopamine fun. The result? Tropine goodies even more selective for the dopamine receptors and less for the cholinergic receptors than cocaine. It seems to make perffect sense that these drugs should be highly pleasurable, yet no real discussion of them has taken place anywhere.

I'm no pharmacological expert; just a humble organic chemist. My understandings of this subject are rather general. Would anyone be willing to venture a hypothesis why these drugs aren't looked at with closer scrutiny by everyone?

For further reading on the subject, inculding pharmacology as well as chemistry, see:

US PAT 2706198; 1952
US PAT 2782200; 1955
US PAT 2799680; 1954
DE PAT 1020634; 1957

Arch.Pharm.(Weinheim) 309; 1976; 234;

J.Med.Chem. 40; 6; 1997; 851-857;
J.Med.Chem. 38; 20; 1995; 3933-3940;

The patents aren't that good. THe main reason I put them in there was to show that these compounds have been around a long time. What's really interesting is the J.Med.Chem articles -- complete with some nice detailed pharmacological comparisons.

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-the good reverend drone

Beagle
Member   posted 02-23-99 01:10 PM          
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You have a knack for picking interesting topics Drone. I've been curious about these compounds since I read that 1 sentence at the end of the cocaine chapter in Psych. Chem. about Benztropine (Cogentin) causing hallucinations.
I've never looked much at these compounds because it seems that they often don't have the same behavioral profile of cocaine. For instance, from a NIDA report:
"Benztropine Analogs Lack Cocaine-like Behavioral Effects Benztropine analogs bind to the dopamine transporter and inhibit dopamine uptake but do not produce behavioral effects similar to those of cocaine. It has been suggested that these compounds lack cocaine-like behavioral effects. Recent studies conducted in the Psychobiology Section show conclusively that antimuscarinic actions potentiate rather than interfere with the expression of cocaine-like behavioral
effects. Therefore, the lack of cocaine-like effects of the benztropine analogs is not
due to antimuscarinic actions, and may better be accounted for by an action at the
dopamine transporter that is distinct from that of cocaine."

I'm not sure about those conclusions, but it illustrates my general feeling that blocking dopamine reuptake doesn't a fun compound make. I really don't understand why, because compounds like this often bind to a different site on the same receptor as cocaine (dopamine transporter complex), but seem to produce the same end result: i.e. more dopamine in the synapse.

This has been seen several times in self-administration studies. In these studies, an animal (often monkey) is trained to inject a drug of known abuse potential. In this case, meth or coke. These studies are brutal to me. The animal is totally restrained, and trained to press a lever in order to recieve an automatic injection from an indwelling cannula. Often, he will have to press the lever many, many times to get the fix. After the monkey is good and hooked, another drug that is being evaluated for similar abuse potential is substituted. If he will similarly press a lever constantly for the reward, the drug is judged to have a similar abuse potential.

I have mixed feelings about how to evaluate the results of these nazi death camp experiments. If you were to compare coke and meth by this method, you could certainly tell that both are addictive and will substitute for each other. On the other hand, the animals are in such physical and mental stress that it seems likely that they would accept any small amount of stimulus that would distract them from their surroundings. Even monkeys will self administer DMT (actually smoke it on lettuce) if they are subjected to severe sensory deprivation. Normally, monkeys have no desire to smoke DMT.

With this in mind, it has been shown that other fairly potent indirect dopamine agonists will not substitute for coke/meth well. Two examples are mazindol, a known anorectic, and GBR-(some code #), a very potent DA reuptake blocker. However, when the low-grade stimulants diethylpropion or ritalin are tested, an appropriate decrease is seen in the rate of acceptance.

Self-administration studies seem not to test whether a compound is abusable, but to prove that it is. There is bias built in to produce the desired result. They are generally funded by organizations that wish to further control drugs, and there is no doubt that grant money flows a lot faster to groups that can demonstrate exactly what you want to see, while maintaining an air of objectivity.

For example, see Macenski, M. J. and Meisch, R. A. (accepted) Cocaine self-administration under conditions of restricted and unrestricted food access. Experimental and Clinical Psychopharmacology. Here it was found that
"These data suggest that food restriction increases cocaine's reinforcing
effects and that the higher the cocaine dose, the greater the reinforcing effects. A
demand curve analysis was completed and data are discussed in terms of
micro-economic principles."

Why else would you want to starve the critters before testing, unless it is to produce the desired redult?

Another paper where the title says it all: Macenski, M. J. and Meisch, R. A. (1995) Oral cocaine self-administration in rhesus monkeys: Strategies for engendering reinforcing effects. Experimental and Clinical Psychopharmacology. 3: 129-139.

I haven't looked at those JMC papers yet, so I can't comment on these cpds, but if the study was solely in vitro inhibition of [H3]DA, then the results are ambiguous. Even studies looking at the inhibition of cocaine binding can be misleading since it binds at more than one receptor.

It is nice to have some kind of behavioural profile study too, such as production of stereotyped behavior in rats (increased vigilance, repetitive grooming, etc). These studies can often be misleading too, but they add evidence.

One of the best tools for industrial evaluation of psychotropics is the discrimulative stimulus paramigm. In one variation, rats are trained to press a lever repeatedly to get food. Administration of a training drug is a cue that pressing the lever will dispense food. The control is usually saline solution. Pressing the lever after getting saline will not produce food. Once they are trained to discriminate drug from saline, the compound in question is administered to see if the rats respond appropriately. False positives are not uncommon, because of the complex nature of a psychoactive drug response. False negatives are much more rare, so these studies can be useful for providing leads.

But ultimately, I agree with Shulgin. If you want to find out if something gets you high, a rat is the last person to ask.

But getting to your question of why these cpds aren't looked at more, I think that they are. Quite a bit of research is being done on similar cps at various co's. Of course they are looking for cocaine antagonists or anti-parkinson's agents, etc. But there is much work that could be done on a low scale nonindustrial level. Many of these cpds are fairly simple to synth. And research into superpotent cocaine-like cpds is quite legitimate. By understanding just how coke produces its effects, you might be able to make an antagonist for treating addiction, a compound that would have a tremendous market!

rev drone
Member   posted 02-23-99 04:50 PM          
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Beagle,
True, antimuscarinic activity would indeed potentiate cocaine-related behavior, but I really think the dopamine receptor activity component, not the antimuscarinic component to coke's structural activity relationship is the key to lots of fun, and I still think dopamine activity is still a good indicator for this class of compound (psychedelics are another question altogether.) The behavior of rats on coke isn't necessarily indicative of "a good time", since antimuscarinic drugs aren't really all they're cracked up to be (no pun intended). Think about it. What drugs are antimuscarinics aside from cocaine? Benztropine, scopolamine, muscimole and quinuclidinyl benzylate -- aside from coke, none of these are particularily appealing. It makes perfect sense that any drug with activity akin to these, when combined with a stimulant activity, when injected in a rat, is gonna result in one freaked-out little rodent, who's going to display some rather barroque reactions to this invasion of his receptors. Its the equivalent to turning his picture of the world on its side while letting the v-hold slip, as someone pushes the fast-forward button.

Now I'm skeptical about the mazindol thing. I've read evidense that it was abused from time to time (not like meth, but perhaps more like pemoline. In Switzerland, specificly.) I know about the GBR #"""" drug as well, but I'd never heard the final word on it. Do you have references to back up these claims?

The stuff is incredibly easy to synth -- tropine plus the chloro diphenyl methane of your choice.

------------------
-the good reverend drone

 
Beagle
Member   posted 02-25-99 12:34 PM          
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Of course I was not suggesting that antimuscarinic activity is useful to predict cocaine-like profile of a cpd. The statement that antimuscarinic cpds potentiate cocaine-like effects really means little in terms of human pharmacology.
You are correct that mazindol has been abused, although rarely, and in very large doses. Also, it will indeed substitute for amphetamine in self-administration studies, but it is clear that monkeys don't like it nearly as much. In fact, in contrast to what I thought, mazindol may indeed be a good lead compound for development of psychostimulants. In Prog Neuropsychopharmacol Biol Psychiatry 1988 v. 12 p. 233-9, it was found that
"the potencies of cocaine-like drugs in animal studies of drug self-administration are correlated with their potencies in inhibiting 3H-mazindol binding to dopamine transporters"

However, mazindol, GBR-12935, and benztropine like DA uptake inhibitors still seem to lack strong reinforcing properties. This may be due to secondary effects, as pointed out in Mol Pharmacol 1994, v. 45 p. 312-6:
"Dopamine uptake inhibitors had one of three effects on transporter-mediated efflux. Some drugs, in addition to inhibiting uptake, inhibited spontaneous release of dopamine. Drugs in this class included mazindol, GBR-12935, bupropion, nomifensine, and benztropine. All of the drugs with the potential for abuse by humans either enhanced release (methamphetamine, amphetamine, and ethanol) or had no effect on release (phencyclidine, cocaine, and WIN 35,428). The ability to define classes of uptake blockers based on their effects on human transporter-mediated dopamine efflux may lead to the identification of structural features of the transporter that differentiate abused from nonabused drugs."

I can't recall the paper in which I saw that the GBR compound did not have reinforcing properties like cocaine, but I remember being quite puzzled when I saw it, since GBR is such a potent DA reuptake blocker. This may be explained by the Mol. Pharm. paper.

But the benztropine and GBR's are quite easy to synth, and may hold promise. If their cocaine receptor binding profile could be seperated from DA release inhibition, then they might be interesting. Of course this is exactly the opposite of what is being looked at by the pharm companys.

 
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