Opioid Ligands Addressing Unconventional Binding Sites and More Than One Opioid Receptor Subtype

Abstract

Opioid receptors (ORs) represent one of the most significant groups of G‐protein coupled receptor (GPCR) drug targets and also act as prototypical models for GPCR function. In a constant effort to develop drugs with less side effects, and tools to explore the ORs nature and function, various (poly)pharmacological ligand design approaches have been performed. That is, besides classical ligands, a great number of bivalent ligands (i. e. aiming on two distinct OR subtypes), univalent heteromer‐selective ligands and bitopic and allosteric ligands have been synthesized for the ORs. The scope of our review is to present the most important of the aforementioned ligands, highlight their properties and exhibit the current state‐of‐the‐art pallet of promising drug candidates or useful molecular tools for the ORs.

Designing drugs and chemical probes with the dualsteric approach

“…The dualsteric approach 31 is an emerging pharmacological technique in the past twenty years. Compared to classical orthosteric or allosteric modulators, 15 dualsteric modulators simultaneously bind to orthosteric and allosteric sites.…”

“…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.…”

A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse

“…65,113 In addition, many bivalent ligands aiming at different opioid receptors have been designed and developed. 285 These bivalent ligands consist of two different pharmacophores (agonists or antagonists, connected via a linker) targeting two different receptors. The bivalent ligands targeting KOR can produce similar potential therapeutic benefits to those of mixed KOR agonists while also lacking the typical side effects of pure KOR agonists.…”

“…These bivalent ligands consist of two different pharmacophores targeting two different receptors; the two pharmacophores are connected via a linker (also called a spacer). 285 The pharmacophores could be agonists or antagonists of these receptors. 285 For example, KDAN-18 (Figure 9) is a bivalent ligand that targets KOR (agonistic) and DOR (antagonistic) 286 and KMN-21 (Figure 9) is a bivalent ligand that targets KOR (antagonistic) and MOR (antagonistic).…”

“…285 The pharmacophores could be agonists or antagonists of these receptors. 285 For example, KDAN-18 (Figure 9) is a bivalent ligand that targets KOR (agonistic) and DOR (antagonistic) 286 and KMN-21 (Figure 9) is a bivalent ligand that targets KOR (antagonistic) and MOR (antagonistic). 287 Additionally, there are other bivalent ligands that selectively target opioid heteromers.…”