Arylcyclohexylamine's complex recreational pharmacophore (DRI, opioid, dissociative)

[Nagelfar]

It has long interested me that the arylcyclohexylamine skeleton of drugs like Ketamine, PCP & Bromadol have instances and permutations that are functional as dopamine reuptake inhibitors, NMDA antagonists (primarily), and opioid mu agonists respectively.

It is conceivable then(?) that a drug could be made of such or a related category of such that is recreational in each respect at once? Which arylcyclohexlamine would be closest to an overlay of functionality inherently significant to all three?

 

[sekio]

PCP and Ketamine hit all 3, AFAIK.

 

[Nagelfar]

Yet primarily dissociative, would there be a way to strengthen a noticeable dopaminergic & opioid effect from those? or does the very dissociative effect seem to 'cancel' out the other two subjectively? I've heard of people IV'ing ketamine & cocaine together for recreational value.

 

[cosmotroniks]

Substituents can alter the relative binding affinities for different receptors, thus producing increased stimulant or opioid effects. For instance, 3-hydroxy phencyclidine -
3-HO-PCP/1-(1-(3-hydroxyphenyl)cyclohexyl)piperidine - has significantly enhanced mu-agonist effects, with about 430 times the affinity of PCP for the mu-opioid receptor.
Also, TCP 1-(1-(2-thienyl)cyclohexyl)piperidine is more stimulating than PCP, and BTCP, 1-(1-benzothiophenyl)cyclohexyl piperidine has primarily stimulant effects,
with relatively insignificant dissociative effects.

 

[fastandbulbous]

BTCP is incredibly hepatotoxic though - at least 1 reported death

 

[NeuroPsyence]

Although the mechanisms you listed are the primary ones that accompany arylcyclohexylamine structure-activity relationships, they are certainly not the only ones. For instance, I believe a recent study demonstrated that Ketamine interacts with both Dopamine D2 and Serotonin 5-HT2a. Don't have the study on hand, but it should be easy to find with a quick search. There's reason to believe that many dissociatives possess subtle iteration with ion channels as well. Food for thought.