You can't just cut and paste molecules together and expect them to exibit activity at both sites. That's why you make two drugs, and take them at the same time
I am aware of this. I only explained it in this manner because I wanted some replies. When I fail to make analogies in my posts, apparantly people don't know what to say (perhaps they cannot identify?) and my threads die into the dust. So I had a genuine idea merely regarding the cyclohexylamine substitute, and decided to show that it was similar to PCP to illustrate why it might have drug action.
Slappy, thank you for your post. You have opened up a can of worms for yourself now. Prepare for the barrage of questions in my next PM. :P
And thank you for the reference, I think I will be able to locate that at my library. I really appreciate this.
PrimoPyro
Vivent Longtemps La Ruche!
Molecular Docking Reveals a Novel Binding Site Model for Fentanyl at the µ-Opioid Receptor
Subramanian, G.; Paterlini, M. G.; Portoghese, P. S.; Ferguson, D. M.
J. Med. Chem. 43(3), 381-391 (2000) (https://www.thevespiary.org/rhodium/Rhodium/pdf/fentanyldocking.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/fentanyldocking.pdf)
DOI:10.1021/jm9903702 (http://dx.doi.org/10.1021/jm9903702)
Abstract
The ligand binding modes of a series of fentanyl derivatives are examined using a combination of conformational analysis and molecular docking to the mu-opioid receptor. Condensed-phase molecular dynamics simulations are applied to evaluate potential relationships between ligand conformation and fentanyl substitution and to generate probable "bioactive" structures for the ligand series. Automated docking of the largely populated solution conformers identified a common binding site orientation that places the N-phenethyl group of fentanyl deep in a crevice between transmembrane (TM) helices II and III while the N-phenylpropanamide group projected toward a pocket formed by TM-III, -VI, and -VII domains. An analysis of the binding modes indicates the most potent fentanyl derivatives adopt an extended conformation both in solution and in the bound state, suggesting binding affinity may depend on the conformational preferences of the ligands. The results are consistent with ligand binding data derived from chimeric and mutant receptor studies as well as structure-activity relationship data reported on a wide range of fentanyl analogues. The binding site model is also compared to that of N-phenethylnormorphine. An overlay of the bound conformation of the opiate and cis-3-methylfentanyl shows the N-phenethyl groups occupy equivalent binding domains in the receptor. While the cationic amines of both ligand classes were found docked to an established anchor site (D149 in TM-III), no overlap was observed between the N-phenylpropanamide group and the remaining components of the opiate scaffold. The unique binding mode(s) proposed for the fentanyl series may, in part, explain the difficulties encountered in defining models of recognition at the mu-receptor and suggest opioid receptors may display multiple binding epitopes. Furthermore, the results provide new insight to the design of experiments aimed at understanding the structural basis to the differential selectivities of ligands at the mu-, sigma-, and kappa-opioid receptors.
4-(2-Fluoro-phenyl)-1-(1-phenyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridine
Developed by Grünenthal (those who developed tramadol) as a ligand for the PCP and µ-opioid receptor. It binds to both receptors with approximately the same affinity, therefore is, at an active dose, both an NMDA antagonist and a µ-agonist. Ref: Patent WO0220481 (http://l2.espacenet.com/dips/viewer?PN=WO0220481&CY=gb&LG=en&DB=EPD)
Dr. Heckyll & Mr. Jive by Men at Work
...tells my tale.