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.
Highlights
This paper focuses on the observation that combinations of adrenergic and opioid drugs often display significantly enhanced activity that involves improved efficacy at lower drug dosages, increased duration of drug activity, and prevention of the development of tolerance
The resulting compound, KDN-21, stabilized the heterodimer resulting in greatly enhanced function [151,152]. Another example of a dimerization-enhancing bitopic, tethered drug is provided by Peng et al [127], who designed bivalent ligands containing butorphan linked to nalbuphine, naltrexone, or naloxone with varying degrees of specificity and activity at mu opioid receptors (MOR), delta-opioid receptors (DOR) and KOR
While design of tethers for optimizing heterodimerization will naturally focus on linkers that place both the opioid and adrenergic modules in their respective orthosteric binding sites, it is likely that further enhancement of receptor activity will result from binding of the tethered drug to the extracellular allosteric sites as well. (NOT SHOWN) It may be possible to combine the two approaches to biotopic drug design shown here to link the type of short-tethered bitopic drugs shown on the left with long linkers such as those illustrated on the right to produce drugs that optimize binding to receptor orthosteric and allosteric sites simultaneously with optimizing heterodimerization of receptors
Summary
This paper focuses on the observation that combinations of adrenergic and opioid drugs often display significantly enhanced activity that involves improved efficacy at lower drug dosages, increased duration of drug activity, and prevention of the development of tolerance. An additional risk of combining opioids with adrenergic drugs is the cross-tolerance that develops between the drugs, so that over-use of adrenergic agonists can itself lead to withdrawal symptoms [66,67,68] Despite these potential drawbacks, the literature on opioid–adrenergic combinations is broadly positive about their benefits
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