Biased, Bitopic, Opioid–Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction

Abstract

This paper proposes the design of combination opioid–adrenergic tethered compounds to enhance efficacy and specificity, lower dosage, increase duration of activity, decrease side effects, and reduce risk of developing tolerance and/or addiction. Combinations of adrenergic and opioid drugs are sometimes used to improve analgesia, decrease opioid doses required to achieve analgesia, and to prolong the duration of analgesia. Recent mechanistic research suggests that these enhanced functions result from an allosteric adrenergic binding site on opioid receptors and, conversely, an allosteric opioid binding site on adrenergic receptors. Dual occupancy of the receptors maintains the receptors in their high affinity, most active states; drops the concentration of ligand required for full activity; and prevents downregulation and internalization of the receptors, thus inhibiting tolerance to the drugs. Activation of both opioid and adrenergic receptors also enhances heterodimerization of the receptors, additionally improving each drug’s efficacy. Tethering adrenergic drugs to opioids could produce new drug candidates with highly desirable features. Constraints—such as the locations of the opioid binding sites on adrenergic receptors and adrenergic binding sites on opioid receptors, length of tethers that must govern the design of such novel compounds, and types of tethers—are described and examples of possible structures provided.

Perioperative Management of a Pediatric Patient with Beckwith–Wiedemann Syndrome Undergoing a Partial Glossectomy According to Egyedi/Obwegeser

“…Furthermore, by exploiting the pharmacodynamics of Dexmetomidine, we obtain a valid sedation while maintaining spontaneous breathing. As regards Remifentanil being an insensitive context drug with a very rapid off-set, we have the possibility of modulating analgesia and reducing or increasing the dosage in a continuous infusion without the problem of accumulation or excessive respiratory depression [ 23 ]. Paracetamol was imbricated following extubation, in the control of post-operative analgesia, by administering 350 mg intravenously up to three times a day, observing a valid result.…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…The choice of these receptors is due to rather extensive information about their allosteric sites and the diversity of their endogenous and synthetic allosteric regulators, including autoantibodies and synthetic pepducins. At the same time, for a number of other GPCRs, there is also a lot of data on allosteric regulation and their analysis is presented in a number of recent comprehensive reviews and analytical articles: for muscarinic acetylcholine receptors [ 171 , 172 , 173 , 174 ], for metabotropic glutamate receptors [ 171 , 175 , 176 ], for 5-hydroxytryptamine (serotonin) receptors [ 177 , 178 ], for dopamine receptors [ 177 , 179 ], for opioid receptors [ 178 , 180 , 181 ], for cannabinoid receptors [ 176 , 182 , 183 , 184 ], for adenosine receptors [ 185 ], for neuropeptide Y receptors [ 186 ], for melanocortin receptors [ 186 ], for angiotensin receptors [ 187 ], for glucagon-like peptide-1 receptors [ 176 , 188 ], and for free fatty acid receptors [ 58 ].…”

Designing drugs and chemical probes with the dualsteric approach

“…Firstly, as the mechanism of allosteric drugs is not as direct as orthosteric drugs, so they are usually less potent. [29][30][31] Therefore, it seems hard to simultaneously improve the potency and selectivity in drug design when targeting only one site. Secondly, there is no reason why mutations would not appear in allosteric sites under the selection of drugs.…”