Clinical data | |
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Other names | WW-12 (patent) [1] |
Drug class | ACKR3 (CXCR7) agonist; Opioid modulator |
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PubChem CID | |
Chemical and physical data | |
Formula | C21H28N2O |
Molar mass | 324.468 g·mol−1 |
3D model (JSmol) | |
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RTI-5152-12, or WW-12 (in patent), is a synthetic small-molecule agonist of the atypical chemokine receptor ACKR3 (CXCR7) that was derived from the naturally occurring alkaloid conolidine. [2] [3] [4] [1] RTI-5152-12 has 15-fold improved potency towards ACKR3 relative to conolidine. [2] [3] [1]
ACKR3 is a novel opioid receptor which functions as a broad-spectrum trap or scavenger for endogenous opioid peptides, including enkephalins, dynorphins, and nociceptin. [2] [5] The receptor acts as a negative modulator of the opioid system by decreasing the availability of opioid peptides for their classical receptors like the μ-opioid receptor. [2] [5] Ligands of ACKR3, by competitively displacing endogenous opioid peptides from ACKR3, can potentiate the actions of these endogenous opioids and produce effects like analgesia and anxiolysis in animals. [2] [3]
RTI-5152-12 is being developed as a potential pharmaceutical drug and, as of December 2021, is in the preclinical stage of development for treatment of pain. [6] [7] [4] The chemical structure was not disclosed until a patent was published in June 2022. [8] [3]
Endorphins are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogenous painkillers often produced in the brain and adrenal medulla during physical exercise or orgasm and inhibit pain, muscle cramps, and relieve stress.
Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neoendorphin. Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal. Occasionally, prodynorphin is not fully processed, leading to the release of "big dynorphin". "Big dynorphin" is a 32-amino acid molecule consisting of both dynorphin A and dynorphin B.
Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind as ligands to the body's opioid receptors. Discovered in 1975, two forms of enkephalin have been found, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene.
β-Endorphin (beta-endorphin) is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin.
The periaqueductal gray (PAG), also known as the central gray, is a brain region that plays a critical role in autonomic function, motivated behavior and behavioural responses to threatening stimuli. PAG is also the primary control center for descending pain modulation. It has enkephalin-producing cells that suppress pain.
Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble those of opiates. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, control of food intake, and the rewarding effects of alcohol and nicotine.
Nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor. Nociceptin acts as a potent anti-analgesic, effectively counteracting the effect of pain-relievers; its activation is associated with brain functions such as pain sensation and fear learning.
The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.
Endomorphins are considered to be natural opioid neuropeptides central to pain relief. The two known endomorphins, endomorphin-1 and endomorphin-2, are tetrapeptides, consisting of Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Phe amino acid sequences respectively. These sequences fold into tertiary structures with high specificity and affinity for the μ-opioid receptor, binding it exclusively and strongly. Bound μ-opioid receptors typically induce inhibitory effects on neuronal activity. Endomorphin-like immunoreactivity exists within the central and peripheral nervous systems, where endomorphin-1 appears to be concentrated in the brain and upper brainstem, and endomorphin-2 in the spinal cord and lower brainstem. Because endomorphins activate the μ-opioid receptor, which is the target receptor of morphine and its derivatives, endomorphins possess significant potential as analgesics with reduced side effects and risk of addiction.
Opiorphin is an endogenous chemical compound first isolated from human saliva. Initial research with mice shows the compound has a painkilling effect greater than that of morphine. It works by stopping the normal breakup of enkephalins, natural pain-killing opioids in the spinal cord. It is a relatively simple molecule consisting of a five-amino acid polypeptide, Gln-Arg-Phe-Ser-Arg (QRFSR).
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(mu)-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium and for which the receptor was named, with mu being the first letter of Morpheus, the compound's namesake in the original Greek. It is an inhibitory G-protein coupled receptor that activates the Gi alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.
The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.
Naltrindole is a highly potent, highly selective delta opioid receptor antagonist used in biomedical research. In May 2012 a paper was published in Nature with the structure of naltrindole in complex with the mouse δ-opioid G-protein coupled receptor, solved by X-ray crystallography.
Atypical chemokine receptor 3 also known as C-X-C chemokine receptor type 7 (CXCR-7) and G-protein coupled receptor 159 (GPR159) is a protein that in humans is encoded by the ACKR3 gene.
RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research.
Neoendorphins are a group of endogenous opioid peptides derived from the proteolytic cleavage of prodynorphin. They include α-neoendorphin and β-neoendorphin. The α-neoendorphin is present in greater amounts in the brain than β-neoendorphin. Both are products of the dynorphin gene, which also expresses dynorphin A, dynorphin A-(1-8), and dynorphin B. These opioid neurotransmitters are especially active in Central Nervous System receptors, whose primary function is pain sensation. These peptides all have the consensus amino acid sequence of Try-Gly-Gly-Phe-Met (met-enkephalin) or Tyr-Gly-Gly-Phe-Leu ( leu-enkephalin). Binding of neoendorphins to opioid receptors (OPR), in the dorsal root ganglion (DRG) neurons results in the reduction of time of calcium-dependent action potential. The α-neoendorphins bind OPRD1(delta), OPRK1(kappa), and OPRM1 (mu) and β-neoendorphin bind OPRK1.
Conolidine is an indole alkaloid. Preliminary reports suggest that it could provide analgesic effects with few of the detrimental side-effects associated with opioids such as morphine, though at present it has only been evaluated in mouse models.
Endomorphin-2 (EM-2) is an endogenous opioid peptide and one of the two endomorphins. It has the amino acid sequence Tyr-Pro-Phe-Phe-NH2. It is a high affinity, highly selective agonist of the μ-opioid receptor, and along with endomorphin-1 (EM-1), has been proposed to be the actual endogenous ligand of this receptor (that is, rather than the endorphins). Like EM-1, EM-2 produces analgesia in animals, but whereas EM-1 is more prevalent in the brain, EM-2 is more prevalent in the spinal cord. In addition, the action of EM-2 differs from that of EM-1 somewhat, because EM-2 additionally induces the release of dynorphin A and [Met]enkephalin in the spinal cord and brain by an unknown mechanism, which in turn activate the κ- and δ-opioid receptors, respectively, and a portion of the analgesic effects of EM-2 is dependent on this action. Moreover, while EM-1 produces conditioned place preference, a measure of drug reward, EM-2 produces conditioned place aversion, an effect which is dynorphin A-dependent. Similarly to the case of EM-1, the gene encoding for EM-2 has not yet been identified.
LIH383 is an octapeptide and highly potent and selective agonist of the atypical chemokine receptor ACKR3 (CXCR7) that was derived from the opioid peptide adrenorphin. ACKR3 is a novel opioid receptor which functions as a broad-spectrum trap or scavenger for endogenous opioid peptides, including enkephalins, dynorphins, and nociceptin, and thereby acts as a negative modulator of the opioid system. By displacing them from ACKR3 and thereby increasing their availability, LIH383 potentiates the actions of endogenous opioids, for instance their analgesic effects. Other ligands of ACKR3 include conolidine, CCX771, RTI-5152-12, and VUF15485.
Interestingly, ACKR3 has recently been demonstrated to be the main GPCR target of conolidine (Szpakowska et al., 2021), a natural analgesic alkaloid found in the bark of the tropical flowering shrub Tabernaemontana divaricate, which is used in traditional Chinese medicine to treat fever and pain (Tarselli et al., 2011). [...] Systematic chemical modifications of conolidine resulted in a analogue compound, RTI-5152-12, with 15-fold improved potency towards ACKR3. Notably, conolidine and RTI-5152-12 function similarly to LIH383 and conolidine's analgesic activity was proposed to rely on the inhibition of the scavenging functions of ACKR3 increasing the availability of analgesia-inducing endogenous opioid peptides for the classical ORs.
The researchers also developed a synthetic analog of conolidine, RTI-5152-12, which displays an even greater activity on the receptor. [...] In parallel to characterizing the interaction between conolidine and ACKR3, the two teams went a step further. The scientists developed a modified variant of conolidine — which they called "RTI-5152-12" — which exclusively binds to ACKR3 with an even higher affinity. Like LIH383, a patented compound previously developed by Dr. Andy Chevigné and his team, RTI-5152-12 is postulated to increase the levels of opioid peptides that bind to classical opioid receptors in the brain, resulting in heightened painkilling activity. The LIH-RTI research teams established a collaboration agreement and filed a joint patent application in December 2020.
A recent elegant study has provided extensive evidence that ACKR3 is a chemokine receptor with the ability to bind opioid peptides; however, opioid binding did not trigger downstream signaling through this receptor [21]. Thus, it is suggested that ACKR3 serves scavenger functions for many opioids, especially enkephalins and dynorphins, by reducing their availability for their classical opioid receptors [21]. Accordingly, treatment with ACKR3 agonist LIH383, even at high concentration, did not produce any electrophysiological effect in PAG neurons, confirming the scavenging function of ACKR3 in this brain region.
Some of the other emerging pain management candidates in development include AT-121, ML-351, RTI-5152-12, and a Nav1.7 gene therapy. All of these potential therapies are in preclinical research.
The scientists also extended their findings by chemically modifying conolidine to create a new compound, RTI-5152-12, which binds specifically to the ACKR3 receptor. In comparison with the natural conolidine, this synthetic compound showed increased binding to the ACKR3 receptor, making it a more effective potential treatment option. According to the LIH press release, the two research teams filed a joint patent application for RTI-5152-12 in December 2020. The study authors state: "Overall, the discovery of the potential mode of action of conolidine and its activity on ACKR3 is a significant step forward toward a more exhaustive understanding of its role in pain regulation, bearing great potential for novel drug development against chronic pain."
In 2021, Szpakowska et al. disclosed conolidine and the chemically optimized RTI-5152-12 as opioid scavengers for ACKR3.45 The authors claimed that a patent application was filed; however, the patent is not publicly available yet (patent databases accessed on 23 05-2022).