Obscure and Unknown: Tricyclic Arylcyclohexylamines

*WARNING* The substances mentioned in this series have little to no record of human use, and thus the effects they have on humans are either poorly understood or entirely unknown. Much of what this information is simply hypotheses based on animal trials or very small human sample sizes. Very little information exists about their acute or long-term toxicity. Under no circumstances should any of these substances be ingested by a human outside of a clinical setting where psychological and physiological effects can be closely monitored and extremely precise doses can be prepared and TITRATED. DO NOT seek any of these out if you do not have access to those resources.

Today we'll be taking a brief look at two very potent and little known dissociatives, only known by the names PD-137889 and PD-PD-138289. This posts continued the theme in the last post of conformationally constrained heterocyclic ring structures built off the backbone of familiar drugs, more specifically tricyclic structures. 

PD-137889

PD-137889

PD-137889 is considered a conformationally constrained Arylcyclohexylamines, bearing the fundamental structure of a cylclohexane with a phenyl ring and some sort of amine group bonded to the same spot. It differs from the familiar Arylcyclohexylamines in having a carbon bridge the gap between the two rings, bonded to both of them, holding them both in place and forming a 5 carbon ring in between them. PD-137889 is referred to structurally as a fluorenamine.

There is no record of human tests of either compound. All information on them compound is pulled from receptor assays and animal studies. Similar to most other known dissociatives, it serves as an NMDA receptor channel blocker, meaning it literally wedges itself into the NMDA receptor and blocks it1. This is the same mechanism by which drugs like ketamine and PCP work.

One study found racemic PD-137889 to have a similar NMDA receptor affinity to PCP, with an IC50 of about 30 nM (vs. PCP's 36.5)2. By this measure, a lower IC50 is demonstrated to yield a higher potency, so this compound can be expected to be slightly more potent than PCP, with a dose of less than 10 mg, though this is subject to the pharmacokinetics of the compound. A unnamed variant of this with an ethylamine group vs. the methylamine group seen in PD-137889 was demonstrated to have an even higher affinity in this study, suggesting a range of analogues using this constrained arylcyclohexylamine backbone with a high potency2.

Of course not all NMDA antagonists yield dissociative anesthetic effects. PD-137889 however showed promise in its similarity to PCP in animal discrimination studies, where rats trained to identify PCP responded in the same way to PD-137889, meaning that it probably had similar subjective effects1. Of course this cannot be known for sure until tests are done in humans.

PD-138289

PD-138289

Other variations on the theme suggested similar receptor blocking activity with a constrained structure using a 6 membered ring between the cyclohexane and phenyl ring, labeled as PD-1382893. This structure is referred to as a phenanthrenamine. PD-138289 was demonstrated to have identical effects to PD-138289 and PCP in an animal discrimination study and a similar receptor affinity to PD-1378891.

A review also suggested efficacy in ring structures of other atoms such as oxygen or sulfur, producing a Tetrahydrofuran or a Thiolane ring in the middle respectively3. This suggests that there are perhaps many variations on a constrained arylcyclohexylamine structure that can yield a variety of potent dissociatives as analogues to the simple PD-137889.


Sources and Further Reading:
1-Nicholson KL, Balster RL (2003) Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats. Psychopharmacology (Berl). 170(2):215-224
2-Hays SJ, Novak PM, Ortwine DF, Bigge CF, Colbry NL, Johnson G, Lescosky LJ, Malone TC, Michael A (1993) Synthesis and pharmacological evaluation of hexahydrofluorenamines as noncompetitive antagonists at the N-methyl-D-aspartate receptor. Journal of Medicinal Chemistry 36 (6): 654-670
3-Bigge CF, Malone TC (1993) Overview: Agonists, Antagonists and Modulators of the N-methyl-D-aspartic acid (NMDA) and α-amino-3-hydroxy-5- methyl-4-isoxazolepropanoic acid (AMPA) Subtypes of Glutamate Receptors. Current Opinion on Therapeutic Patents 3(7): 951-989