Ulterior motives in published organic-chemical papers.

[Nagelfar]

It stuck me that a compound that should be very efficacious in Singh's "cocaine antagonist" paper is shown as not being so.

Then it struck me, the "piperidine homologues" he made of cocaine are the para-iodo. Why? Regular cocaine with an iodine at the 4' position has a similarly high ICfifty. If glanced over and this weren't noticed, one might think the (presumably easier to synth from scratch) piperidine homologues of cocaine weren't worth the effort. But comparing how the iodo group gimps binding, it's no worse in doing so for regular cocaine than for the homologues. Without that, these could be highly effective compounds. Perhaps if this were an obvious good route for a ligand, people in positions such as Singh who can acquire the proper ecgonine precursors and do the more complex synthesizing of full-on cocaine may be put at a compromised position with future research if it becomes open to make compounds that are easier to synth and have much the same effect. Besides radio-ligand binding, would there be another reason the iodo would be made in these instances?

Anyone have a source for those homologues and their binding values without the para-iodine?

 

[serotonin2A]

He's trying to identify cocaine antagonists. The iodo analogs of cocaine seemed like they might be effective antagonists.

 

[dopamimetic]

Is a direct cocaine antagonist possible without ending up with something like reserpine (a monoamine depleting drug)?

 

[serotonin2A]

Is a direct cocaine antagonist possible without ending up with something like reserpine (a monoamine depleting drug)?

Theoretically, if you could occupy the cocaine binding site on DAT without mimicking the effects of cocaine on dopaminergic transmission then you might be able to attenuate the effects of cocaine.

 

[dopamimetic]

Hmm yeah, just thought about naloxone that's also blocking endorphins (but it's an inverse agonist in the end, not an antagonist) and while many people seem to tolerate naloxone / naltrexone as long as they aren't on opioids, these agents can and do induce intense dysphoria for some ... I've learned this the hard way when I've tried to crush a tilidine / naloxone pill, naively thinking that the naloxone would only work when IV'd. I had no opioid tolerance, never had before, but this was when I experienced what opiate w/d feels like (as I could confirm later to some extent - but the naloxone is worse, it hits faster and harder).

But so it'd be possible to kick the cocaine off the DAT while preserving it's natural functions to take DA up?

 

[serotonin2A]

Hmm yeah, just thought about naloxone that's also blocking endorphins (but it's an inverse agonist in the end, not an antagonist) and while many people seem to tolerate naloxone / naltrexone as long as they aren't on opioids, these agents can and do induce intense dysphoria for some ... I've learned this the hard way when I've tried to crush a tilidine / naloxone pill, naively thinking that the naloxone would only work when IV'd. I had no opioid tolerance, never had before, but this was when I experienced what opiate w/d feels like (as I could confirm later to some extent - but the naloxone is worse, it hits faster and harder).

But so it'd be possible to kick the cocaine off the DAT while preserving it's natural functions to take DA up?

I don't think it would allow DAT to operate normally. Pure DAT blockade doesn't seem to be very psychoactive -- there has been speculation that cocaine acts by driving DAT into a different functional state.

The idea with the cocaine antagonist is similar to how you can't get a rush with iv cocaine if you've already snorted some.

 

[Nagelfar]

But so it'd be possible to kick the cocaine off the DAT while preserving it's natural functions to take DA up?

Singh didn't seem to be able to discover one, but SoRI-20041 appears to be something interesting along those lines; though for DRAs and not DRIs

He's trying to identify cocaine antagonists. The iodo analogs of cocaine seemed like they might be effective antagonists.

Well, yes, OK I concede, I was looking into it with my own warped googles but with how straight forward he compares it to the para-iodo-benzoyl-methyl-ecgonine, I suppose I am just looking for a scapegoat for wondering what the non-iodo "homologue" (thinking of 'homologue' in the strict sense was meant to be a compound with the same number of bonds or directly comparable structure i.e. non-substituted otherwise) of the piperidine would do without further qualification. ;-P