Beenhead said:
The mere fact that one is connected to the other would make sure that neither side of the molecule could fit into its respective active site. To fit into a protein, you must be able to link into the active site in three dimensions, I believe this would block binding.
I would definitively disagree. Although sterical demand
could disrupt affinity of the compound to its target (receptor, enzyme, whatever), this is not a general rule.
Rather the contrary is true. There are several examples known, where 2 molecules were succesfully combined to yield a more active congener. See e.g.:
Journal of Heterocyclic Chemistry 1983, 20(4), p.1031
"Synthesis and characterization of 5H-1,3-dioxolo[4,5-f]indoleethylamines."
The authors synthesized these compounds:
...and they retained activity. (no idea if full or just partially).
Beenhead said:
I dont want to sound mean, but I think it was a hypthetical linkage of one stimulant to another, without a proper look at binding. Like if you could attach a psilocybin molecule to a DMT molecule would you create a super Psychedelic.
Is the last sentence a question or a statement?
Because it could actually work. See here:
"Inhibition of serotonin 5-hydroxytryptamine2C receptor function through heterodimerization : Receptor dimers bind two molecules of ligand and one G-protein"
HERRICK-DAVIS Katharine ; GRINDE Ellinor ; HARRIGAN Timothy J. ; MAZURKIEWICZ Joseph E. ;
Abstract
Although dimerization appears to be a common property of G-protein-coupled receptors (GPCRs), it remains unclear whether a GPCR dimer binds one or two molecules of ligand and whether ligand binding results in activation of one or two G-proteins when measured using functional assays in intact living cells. Previously, we demonstrated that serotonin 5-hydroxytryptamine2C (5-HT2C) receptors form homodimers (Herrick-Davis, K., Grinde, E., and Mazurkiewicz, J. (2004) Biochemistry 43, 13963-13971). In the present study, an inactive 5-HT2C receptor was created and coexpressed with wild-type 5-HT2C receptors to determine whether dimerization regulates receptor function and to determine the ligand/dimer/G-protein stoichiometry in living cells. Mutagenesis of Ser138 to Arg (S138R) produced a 5-HT2C receptor incapable of binding ligand or stimulating inositol phosphate (IP) signaling. Confocal fluorescence imaging revealed plasma membrane expression of yellow fluorescent protein-tagged S138R receptors. Expression of wild-type 5-HT2C receptors in an S138R-expressing stable cell line had no effect on ligand binding to wild-type 5-HT2C receptors, but inhibited basal and 5-HT-stimulated IP signaling as well as constitutive and 5-HT-stimulated endocytosis of wild-type 5-HT2C receptors. Ml muscarinic receptor activation of IP production was normal in the S138R-expressing cells. Heterodimerization of S138R with wild-type 5-HT2C receptors was visualized in living cells using confocal fluorescence resonance energy transfer (FRET). FRET was dependent on the donor/acceptor ratio and independent of the receptor expression level. Therefore, inactive 5-HT2C receptors inhibit wild-type 5-HT2Creceptor function by forming nonfunctional heterodimers expressed on the plasma membrane. These results are consistent with a model in which one GPCR dimer binds two molecules of ligand and one G-protein and indicate that dimerization is essential for 5-HT receptor function.
The Journal of biological chemistry 2005,
280(48 ), p.40144
Both DMT and psilocine work mainly via GPCRs.
Just recently I have seen an example where an academic research group (Gmeiner, Uni Erlangen/Nuremberg, Germany) prepared bivalent dopamin ligands (2 times the same ligand, connected via long alkyl chains) and they showed a remarkable activity.
Another ref about GPCR-dimers as the active conformers:
Life Science,
2003,
74, p.173.
Abstract
G protein-coupled receptors (GPCRs) form homo-oligomeric and hetero-oligomeric complexes. This understanding has prompted a re-evaluation of many aspects of GPCR biology, however the concept of receptor complexes has not been fully integrated into the current thinking about GPCR structure and function. Nevertheless, receptor oligomerization is a pivotal aspect of the structure and function of GPCRs that has been shown to have implications for receptor trafficking, signaling, and pharmacology and more intricate models for understanding the physiological roles of these receptors are emerging. Here, we summarize some of the advances made in understanding the structural basis and the functional roles of homo- and hetero- oligomerization in this important group of receptors. Although this discussion focuses primarily on the dopamine receptors, particularly the D2 dopamine receptor, and the opioid and serotonin receptors, we discuss the principles governing the oligomerization of all rhodopsin-like GPCRs and potentially of the entire superfamily of these receptors.
Peace! Murphy
Edit: Corrected only some typos...
