Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures.
Peptidomimetics are synthetically altered peptides with adjusted molecular properties for specific biological or therapeutic applications and have been an important class of drug molecules due to their potential features, high potency, and low toxicity since the term was created first in the late 1970s. Although endogenous opioid peptides such as endorphin (END), enkephalins (ENKs), and dynorphins (DYNs) play various complex roles in the body, they have been shown to have a key role in regulating pathological states of pain as well as in multiple behavioral processes: addiction, reward, sedation, and depression. Their activities in the central nervous system (CNS) have been of particular interest for the treatment of pain, considering the centrally mediated actions of the pain process. Despite their critical roles, the endogenous peptides have limited clinical use due to their lack of drug-like properties: low metabolic stability, poor bioavailability, and low blood-brain barrier (BBB) permeability.
To overcome the intrinsic disadvantages and to optimize the therapeutic potential, various strategies have been applied to the design of novel opioid peptidomimetics through in-depth structural analyses and structure–activity relationships (SAR) studies while maintaining key structural features responsible for the biological activity. These, in general, include deletion, addition and/or replacement of certain natural amino acids with non-natural amino acids, and introduction of steric constraints into flexible peptide bonds, which resulted in the discovery of various new opioid peptidomimetic structures with enhanced efficacy and therapeutic potentials.
This article reviews the current development of opioid peptidomimetics from the pharmacological and chemical points of view, which aims toward the development of opioid peptide-derived therapeutics for the treatment of pain. It includes typical mimetic strategies of which the representative molecules with drug-like agonist or antagonist activity are selected and discussed. Emphasis is given to the relatively short length (up to around ten residues) of structures with high receptor selectivity and potency or unique biological profile.
In the following second chapter of this review, opioid receptors and natural peptides are described together with a brief introduction about the discovery and progress. The third chapter covers pharmacological and chemical structural aspects of opioid peptidomimetics. In the former part, pharmacological efforts aimed at developing molecules with enhanced biological activity, receptor selectivity, metabolic stability, BBB permeability, and oral bioavailability are discussed together with successful examples. In the latter part, chemical aspects of opioid peptidomimetics are discussed based on various structural approaches and representative molecules. Starting with the introduction of the well-known “message–address” concept for the opioid receptor-peptide interactions, the part discusses opioid peptidomimetics at MOR, DOR, and KOR for which the relationships to natural peptide scaffolds and activities have been established. The part also outlines useful tools for the opioid peptidomimetic design: local modifications, global restrictions, and secondary structure mimetics. These include the cyclization, N/C-terminal modifications, peptide linking, local backbone modifications, simple non-natural amino acid replacements, etc. Successful cases are discussed in detail, sometimes with failed ones that are worth introducing. Finally, it details prospective aspects of opioid peptidomimetics as therapeutics aiming to inspire future research.
Opioid receptors which belong to G-protein coupled receptors are known to be involved in pain modulation, numerous physiological functions, and behavioral effects and are characterized in three subtypes, mu- (MOR), delta- (DOR), and kappa-opioid receptor (KOR) with overall 60–65% high structural homology. The extracellular region has much lower homology, and the differences in the region are responsible for the subtype-selectivity of endogenous opioid peptides. There are three main families of the endogenous opioid peptides, END, ENK, and DYN, which are derived from three different precursor proteins, pro-ENK, pro-DYN, and pro-opiomelanocortin, and prefer to bind at the MOR, DOR, and KOR, respectively, with low selectivity but strong analgesic effects in vivo with milder side effects, unlike morphine. Regardless of the receptor selectivity, all of the endogenous opioid peptides share the same N-terminal tetrapeptide sequence (YGGF) that acts as the message part for the receptor, while their C-terminal acts as the address part for selectivity.
Since their discovery, endogenous peptides, mostly smaller peptides, have been studied extensively to discover a safe analgesic with minimal alkaloid opioid-related adverse effects. Although END was found to be the most potent analgesic due to high MOR selectivity, fewer studies have been done due to the relatively larger size. A SAR study of END showed that D Ala substitution at position 2 did not change metabolic stability and biological activity, contrary to the ENK analogs that enhanced the stability and activity.
ENKs that are slightly selective for DOR over MOR have been selected as a good scaffold to modify for druggable molecules due to the small size, lower toxicity, and lack of MOR-caused adverse effects. Activation of DOR with an agonist is not strongly analgesic, like that of MOR, but seems to cause less addictive and relatively fewer severe side effects. C 2,5[D Pen 2, D Pen 5]-ENK (DPDPE), [D Ala 2, D Leu 5]-ENK (DADLE), and [D Ser 2, D Leu 5]-ENK (DSLET) are representative molecules modified from the ENK structure showing enhanced selectivity and affinity with full agonist activity for the DOR. Interestingly, [D Ala 2, NMePhe 4, Gly-ol 5]-ENK (DAMGO) is a highly selective MOR agonist derived from ENK structure as well.
DYNs that are formed by cleavage of the precursor prodynorphin contain a high proportion of basic amino acids and exert their analgesic effects primarily through the KOR with slight selectivity over the other subtypes. Activation of the DYN A/KOR system produces similar actions to other opioids but also opposite ones to those of MOR. The KOR appears to be involved in reward, mood state, and cognitive function in the CNS, and its inhibition by an antagonist has recently drawn more attention as a therapeutic target for the treatment of stress-related mood disorders, drug-seeking, and relapse. Nonetheless, KOR agonists are still useful if the activity is localized in the peripheral region due to the potential to avoid serious central side effect, dysphoria. The selectivity of DYN for the KOR is known to come from C-terminal region including Arg 6 to Lys 11, and DYN A-(1-11) is identified as a short fragment that retains similar KOR agonist activity to that of DYN A. Its further modifications led to the development of potent and selective KOR agonists (ex. N-benzyl[D Pro 10]-Dyn A-(1-11)) as well as antagonists (ex. N-benzyl-c 5,8[D Asp 5, Dap 8]-DYN A-(1-11)-NH 2 (Zyklophin)).
Endomorphin (EM)-1 and -2, which are structurally distinct, are atypical endogenous opioid peptides consisting of more constrained amino acid residues (Pro-Trp and Pro-Phe, respectively) in the middle positions and showing higher MOR selectivity over DOR and KOR. These endogenous peptides are localized in the CNS associated with pain mechanism and in the ending of sensory neurons, and their interactions with the opioid receptors produce clinically effective analgesia, which seems to be dissociated by rewarding, and respiratory depression. However, their low ability to penetrate the BBB and low metabolic stability prohibit therapeutic uses as analgesics, and therefore significant efforts have been made to improve metabolic stability and to obtain longer lasting antinociceptive effects through various modifications. Cyclic EM-1 analogs such as ZH853 (Tyr-c[D Lys-Trp-Phe-Glu]-Gly-NH 2) are recent discoveries showing longer duration of action and effective antinociception in multiple pain models with reduced adverse side effects.
Other naturally occurring peptides are dermorphines (DERs) and deltorphins (DLTs), which are isolated from frog skin and milk peptides and are the most selective for MOR and DOR, respectively. The amino acid sequences of these two peptides are quite different from the other endogenous opioids and have been extensively used as a starting point for the development of highly selective opioid peptidomimetics. The N-terminal tetrapeptide of DERs, YaFG, is a minimum structure for the MOR activity and its modified analog, [D Arg 2, Lys 4]-DER (DALDA), is a highly selective MOR agonist but has a limit in crossing the BBB because of multiple positive charges. DLTs are the most selective naturally occurring opioid peptide with a high affinity and potency for the DOR as well as a high BBB penetration rate.
Structural homology and the natural flexibility of endogenous linear opioid peptides limit their uses for a specific subtype receptor because of the possible interactions with more than one subtype receptors and drastic SAR results caused by subtle structural change. For this reason, selectivity, mostly between MOR and DOR, has been a major problem for the linear opioid peptides, and trem
