The "Research chemicals" section already has opiates that are potentially easy to synthesize and have very interesting morphine-like effects with minimal side and unwanted effects. The minimization of side effects is due to many factors, which I will describe in more detail. μ-opioid receptors are expressed on many cells in many different parts of the body: central and peripheral neurons, neuroendocrine, immune and ectodermal cells. Because of this, long-term opiate therapy has many side effects, which include: tolerance, hyperalgesia, respiratory depression, nausea, constipation, and reinforcing effects. The above side effects lead to addiction, gut dysbiosis, and changes in glial cell function.
It has long been known that many G-protein coupled receptors (GPCRs) can form heterodimers with other GPCRs (including μ-opioid receptors). Heterodimers are of great interest because they provide new functional possibilities: there is an alternative possibility to modulate opioid receptors with the help of allosteric mechanisms. Also, the "signaling" of opioid receptors and their endo/exocytosis can be greatly altered by heterodimerization. It is easy to guess that this creates a new "therapeutic window", which gives the possibility to minimize the side effects. These heterodimers are usually expressed in different parts of the brain, which again creates a new therapeutic window.
It has long been known that many G-protein coupled receptors (GPCRs) can form heterodimers with other GPCRs (including μ-opioid receptors). Heterodimers are of great interest because they provide new functional possibilities: there is an alternative possibility to modulate opioid receptors with the help of allosteric mechanisms. Also, the "signaling" of opioid receptors and their endo/exocytosis can be greatly altered by heterodimerization. It is easy to guess that this creates a new "therapeutic window", which gives the possibility to minimize the side effects. These heterodimers are usually expressed in different parts of the brain, which again creates a new therapeutic window.
1. μ-delta heterodimer. Multiple [1] agonists and antagonists have been found for this heterodimer. Activation of the delta opioid receptor allosterically suppresses the μ-opioid receptor. Accordingly, antagonism to the delta opioid receptor in this dimer - increases [2] the binding capacity of the μ-opioid receptor to the G-protein. Confused? The internalization of this dimer also changes. Some mu agonists (DAMGO, deltorphin II, SNC80, and methadone) induce internalization of both receptors, whereas some agonists (DADPE) do not [3].
The key regulator in the internalization of this heterodimer is RTP4 [3] (golgi chaperone). Delta agonists also lead to internalization of this heterodimer. But delta antagonists (e.g. naltriben mesylate) block endocytosis of this heterodimer. This phenomenon is called "biased antagonism" - when delta-opioid antagonists block endocytosis of the heteroreceptor and in doing so increase signaling through μ-opioid receptors. In order to reduce beta-arrestin binding and increase G-protein binding to this heterodimer, delta antagonists and μ-agonists must be administered simultaneously. In this case, we get [4] the maximum possible analgesia from this heteroreceptor. It has also been shown that with prolonged use of opiates, the number of these heteroreceptors is greatly increased. Perhaps this fact plays some role in opiate tolerance, and one possible way of resolving it is to introduce [5] a special protein that destroys the formation of this heterodimer and also potentiates the analgesia from the μ-agonists.
2. Researchers found [6] that orphan GPR139 coexpresses with the μ-opioid receptor and has an inhibitory effect on it, both suppressing signaling and increasing its internalization. When GPR139 is strongly expressed, the expression of the μ-opioid receptor is strongly reduced. Mice with deleted GPR139 showed hypersensitivity to the analgesic and reinforcing effects of morphine. The GPR139 agonist JNJ-63533054 suppressed μ-agonist analgesia. Interestingly, this investigational substance greatly alleviated opiate withdrawal syndrome. GPR139 antagonists, on the contrary, increase analgesia from μ-agonists and decrease their endocytosis.
3. Vasopressin 1b-μ-opioid heterodimer. AVP (arginine vasopressin) regulates morphine sensitivity and morphine tolerance production. Mice with deleted V1b receptor had increased pain sensitivity and increased sensitivity to morphine, and they produced tolerance much slower. The selective V1b antagonist SSR149415 reduced morphine tolerance production and increased morphine analgesia. Apparently, activation of the V1b receptor plays a major role in beta arrestin binding to this heterodimer.
Thus, agonists of μ-opioid receptor heterodimers are the most promising targets in projects to find and study new psychoactive morphine-like substances (for the Research Chemicals section) that will have equivalent recreational effects and minimal side effects, as well as easy synthesis and availability of precursors.
Used literatureThe key regulator in the internalization of this heterodimer is RTP4 [3] (golgi chaperone). Delta agonists also lead to internalization of this heterodimer. But delta antagonists (e.g. naltriben mesylate) block endocytosis of this heterodimer. This phenomenon is called "biased antagonism" - when delta-opioid antagonists block endocytosis of the heteroreceptor and in doing so increase signaling through μ-opioid receptors. In order to reduce beta-arrestin binding and increase G-protein binding to this heterodimer, delta antagonists and μ-agonists must be administered simultaneously. In this case, we get [4] the maximum possible analgesia from this heteroreceptor. It has also been shown that with prolonged use of opiates, the number of these heteroreceptors is greatly increased. Perhaps this fact plays some role in opiate tolerance, and one possible way of resolving it is to introduce [5] a special protein that destroys the formation of this heterodimer and also potentiates the analgesia from the μ-agonists.
2. Researchers found [6] that orphan GPR139 coexpresses with the μ-opioid receptor and has an inhibitory effect on it, both suppressing signaling and increasing its internalization. When GPR139 is strongly expressed, the expression of the μ-opioid receptor is strongly reduced. Mice with deleted GPR139 showed hypersensitivity to the analgesic and reinforcing effects of morphine. The GPR139 agonist JNJ-63533054 suppressed μ-agonist analgesia. Interestingly, this investigational substance greatly alleviated opiate withdrawal syndrome. GPR139 antagonists, on the contrary, increase analgesia from μ-agonists and decrease their endocytosis.
3. Vasopressin 1b-μ-opioid heterodimer. AVP (arginine vasopressin) regulates morphine sensitivity and morphine tolerance production. Mice with deleted V1b receptor had increased pain sensitivity and increased sensitivity to morphine, and they produced tolerance much slower. The selective V1b antagonist SSR149415 reduced morphine tolerance production and increased morphine analgesia. Apparently, activation of the V1b receptor plays a major role in beta arrestin binding to this heterodimer.
Thus, agonists of μ-opioid receptor heterodimers are the most promising targets in projects to find and study new psychoactive morphine-like substances (for the Research Chemicals section) that will have equivalent recreational effects and minimal side effects, as well as easy synthesis and availability of precursors.
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https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00403
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https://www.pnas.org/doi/full/10.1073/pnas.0307601101
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https://www.pnas.org/doi/10.1073/pnas.0804106105
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https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.06-7793com
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https://www.sciencedirect.com/science/article/pii/S0896627310009864
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https://www.science.org/doi/10.1126/science.aau2078