CCK(2) receptor antagonists potentiate pain relief by MOP receptor agonists. In an attempt to enhance this effect, we prepared bivalent ligands incorporating CCK(2) receptor antagonist and MOP receptor agonist pharmacophores. (9) Ligands with 16- to 22-atom spacers could simultaneously bind both receptors but provided no advantage in activity over individual ligands. We now examine the effect of these ligands on receptor internalization as a mechanism of receptor regulation. We prepared CHO cell lines expressing nonfluorescent halves (YN and YC) of yellow fluorescent protein attached to each receptor. Spatial approximation of constructs was needed to yield fluorescence. Monovalent MOP agonist 1 signaled normally and internalized the MOP receptor. Monovalent CCK(2) antagonist 2 did not stimulate receptor internalization. In the dual receptor-bearing cells, bivalent ligands 3a-c capable of simultaneously binding both receptors resulted in cell surface fluorescence and internalization of the fluorescent complex in a time- and temperature-dependent manner. Bivalent ligand 4 with spacer too short to occupy both receptors simultaneously yielded no signal. Receptor tethering with appropriate bivalent ligands can down-regulate signaling by moving a nonactivated receptor into the endocytic pathway.
"However, bivalent ligands containing a mu agonist and a CCK2 antagonist did cause a BRET response, suggesting that they bound simultaneously to each component of the dimer to promote oligomerization. Similar results were reported by Harikumar et al.  in which a fluorescent complement assay was employed to measure dimer formation and in these studies, the authors were able to fine tune the linker size between the opioid and CCK pharmacophore to measures distances of the ligand parts needed to promote dimer formation. Thus, these studies indicate that dimer formation can be induced by single ligands designed to bind simultaneously to two different receptors and suggest an approach to designing novel drugs based on their selective interaction with oligomers. "
[Show abstract][Hide abstract] ABSTRACT: GPCRs play a critical role in human physiology and are a prime target for drug discovery globally. Novel insights into the functions of GPCRs are providing unique approaches to modulate these proteins to generate unique drug candidates. Next generation ligands include those with novel pharmacologies such as allosteric regulators as well pepducins, that affect the interaction of GPCRs with G proteins, to either block selective receptor signaling pathways or mimic the actions of intracellular domains of receptors, thereby activating GPCRs to signal selectively to intracellular pathways. We will review these new concepts and then discuss how they may be exploited using modern discovery technologies to provide novel drug candidates for the future.
[Show abstract][Hide abstract] ABSTRACT: Bifunctional ligands containing an ester linkage between morphine and the δ-selective pharmacophore Dmt-Tic were synthesized, and their binding affinity and functional bioactivity at the μ, δ and κ opioid receptors determined. Bifunctional ligands containing or not a spacer of β-alanine between the two pharmacophores lose the μ agonism deriving from morphine becoming partial μ agonists 4 or μ antagonists 5. Partial κ agonism is evidenced only for compound 4. Finally, both compounds showed potent δ antagonism.
European Journal of Medicinal Chemistry 02/2011; 46(2):799-803. DOI:10.1016/j.ejmech.2010.12.001 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We synthesized symmetrical and nonsymmetrical triplet drugs with 1,3,5-trioxazatriquinane skeletons. The isolation of key intermediates, oxazoline dimers, made it possible to effectively produce nonsymmetrical triplets. Among the synthesized triplets, KNT-93, composed of three identical opioid μ receptor agonists, showed dose-dependent antinociception via the μ receptor. The effect was 56-fold more potent than that of morphine, a representative μ agonist. The profound analgesic effect induced by KNT-93 might result from simultaneous occupation of three μ opioid receptors.
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