Agonist-antagonist

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Agonist vs. antagonist Agonist & Antagonist.jpg
Agonist vs. antagonist

In pharmacology the term agonist-antagonist or mixed agonist/antagonist is used to refer to a drug which under some conditions behaves as an agonist (a substance that fully activates the receptor that it binds to) while under other conditions, behaves as an antagonist (a substance that binds to a receptor but does not activate and can block the activity of other agonists).

Contents

Types of mixed agonist/antagonist include receptor ligands that act as agonist for some receptor types and antagonist for others [1] or agonist in some tissues while antagonist in others (also known as selective receptor modulators).

Synaptic receptors

For synaptic receptors, an agonist is a compound that increases the activation of the receptor by binding directly to it or by increasing the amount of time neurotransmitters are in the synaptic cleft. An antagonist is a compound that has the opposite effect of an agonist. It decreases the activation of a synaptic receptor by binding and blocking neurotransmitters from binding or by decreasing the amount of time neurotransmitters are in the synaptic cleft. These actions can be achieved via multiple mechanisms. A common mechanism for agonists is reuptake inhibition, where the agonist blocks neurotransmitters from reentering the pre-synaptic axon terminal. This gives the neurotransmitter more time in the synaptic cleft to act on the synaptic receptors. Conversely, antagonists often bind directly to receptors in the synaptic cleft, effectively blocking neurotransmitters from binding.

At the alpha adrenoceptors, (R)-3-nitrobiphenyline is an α2C selective agonist as well as being a weak antagonist at the α2A and α2B subtypes. [2] [3]

Agonist-antagonist opioids

The best known agonist-antagonists are opioids. Examples of such opioids are:

Agonist–antagonist opioids usually have a ceiling effect – over particular dose they don't increase their potency. [7] Hence agonist–antagonist opioids have a lower addiction potential but also lower analgesic efficacy and are more likely to produce psychotomimetic effects. [8]

Agonist–antagonist opioids that activate mu opioid receptors while blocking delta produce analgesia without the development of tolerance. [9]

See also

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

<span class="mw-page-title-main">Agonist</span> Chemical which binds to and activates a biochemical receptor

An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.

<span class="mw-page-title-main">Opioid receptor</span> Group of biological receptors

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.

<span class="mw-page-title-main">Nalbuphine</span> Opioid analgesic

Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain. It is given by injection into a vein, muscle, or fat.

<span class="mw-page-title-main">Opioid antagonist</span> Receptor antagonist that acts on one or more of the opioid receptors

An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors.

<span class="mw-page-title-main">Butorphanol</span> Opioid analgesic

Butorphanol is a morphinan-type synthetic agonist–antagonist opioid analgesic developed by Bristol-Myers. Butorphanol is most closely structurally related to levorphanol. Butorphanol is available as the tartrate salt in injectable, tablet, and intranasal spray formulations. The tablet form is only used in dogs, cats and horses due to low bioavailability in humans.

<span class="mw-page-title-main">Alpha-2 adrenergic receptor</span> Protein family

The alpha-2 (α2) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.

κ-opioid receptor Protein-coding gene in the species Homo sapiens, named for ketazocine

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.

<span class="mw-page-title-main">Endomorphin</span> Chemical compound

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.

μ-opioid receptor Protein-coding gene in the species Homo sapiens, named for its ligand morphine

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.

<span class="mw-page-title-main">Nociceptin receptor</span> Protein-coding gene in the species Homo sapiens

The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.

<span class="mw-page-title-main">Nalfurafine</span> Antipruritic drug

Nalfurafine is an antipruritic that is marketed in Japan for the treatment of uremic pruritus in individuals with chronic kidney disease undergoing hemodialysis. It activates the κ-opioid receptor (KOR) and is potent, selective, and centrally active. It was the first selective KOR agonist approved for clinical use. It has also been dubiously referred to as the "first non-narcotic opioid drug" in history.

<span class="mw-page-title-main">Dezocine</span> Opioid analgesic

Dezocine, sold under the brand name Dalgan, is an atypical opioid analgesic which is used in the treatment of pain. It is used by intravenous infusion and intramuscular injection.

<span class="mw-page-title-main">Oxilorphan</span> Chemical compound

Oxilorphan is an opioid antagonist of the morphinan family that was never marketed. It acts as a μ-opioid receptor (MOR) antagonist but a κ-opioid receptor (KOR) partial agonist, and has similar effects to naloxone and around the same potency as an MOR antagonist. Oxilorphan has some weak partial agonist actions at the MOR and can produce hallucinogenic/dissociative effects at sufficient doses, indicative of KOR activation. It was trialed for the treatment of opioid addiction, but was not developed commercially. The KOR agonist effects of oxilorphan are associated with dysphoria, which combined with its hallucinogenic effects, serve to limit its clinical usefulness; indeed, many patients who experienced these side effects refused to take additional doses in clinical trials.

<span class="mw-page-title-main">Norbinaltorphimine</span> Chemical compound

Norbinaltorphimine is an opioid antagonist used in scientific research. It is one of the few opioid antagonists available that is highly selective for the κ-opioid receptor, and blocks this receptor without affecting the μ- or δ-opioid receptors, although it is less selective in vivo than in isolated tissues. nor-BNI blocks the effects of κ-opioid agonists in animal models, and produces antidepressant and anxiolytic-like effects.

<span class="mw-page-title-main">Xorphanol</span> Opioid analgesic

Xorphanol (INN), also known as xorphanol mesylate (USAN), is an opioid analgesic of the morphinan family that was never marketed.

<span class="mw-page-title-main">Cyprodime</span> Chemical compound

Cyprodime is an opioid antagonist from the morphinan family of drugs.

<span class="mw-page-title-main">Alazocine</span> Synthetic opioid analgesic

Alazocine, also known more commonly as N-allylnormetazocine (NANM), is a synthetic opioid analgesic of the benzomorphan family related to metazocine, which was never marketed. In addition to its opioid activity, the drug is a sigma receptor agonist, and has been used widely in scientific research in studies of this receptor. Alazocine is described as a potent analgesic, psychotomimetic or hallucinogen, and opioid antagonist. Moreover, one of its enantiomers was the first compound that was found to selectively label the σ1 receptor, and led to the discovery and characterization of the receptor.

<span class="mw-page-title-main">Cyclorphan</span> Opioid analgesic

Cyclorphan is an opioid analgesic of the morphinan family that was never marketed. It acts as a μ-opioid receptor (MOR) weak partial agonist or antagonist, κ-opioid receptor (KOR) full agonist, and, to a much lesser extent, δ-opioid receptor (DOR) agonist. The drug was first synthesized in 1964 by scientists at Research Corporation. In clinical trials, it had relatively long duration, good absorption, and provided strong pain relief but produced psychotomimetic effects via KOR activation, so its development was not continued.

<span class="mw-page-title-main">Ketorfanol</span> Chemical compound

Ketorfanol, or ketorphanol, is an opioid analgesic of the morphinan family that was found to possess "potent antiwrithing activity" in animal assays but was never marketed. It is a 17-cycloalkylmethyl derivative of morphinan and as such, is closely related structurally to butorphanol, cyclorphan, oxilorphan, proxorphan, and xorphanol, which act preferentially as κ-opioid receptor agonists and to a lesser extent as μ-opioid receptor partial agonists/antagonists.

References

  1. ↑ Hoskin PJ, Hanks GW (March 1991). "Opioid agonist-antagonist drugs in acute and chronic pain states". Drugs. 41 (3): 326–44. doi:10.2165/00003495-199141030-00002. PMID   1711441. S2CID   27694903.
  2. ↑ Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, et al. (August 2007). "Alpha2-adrenoreceptors profile modulation. 3.1 (R)-(+)-m-nitrobiphenyline, a new efficient and alpha2C-subtype selective agonist". Journal of Medicinal Chemistry. 50 (16): 3964–8. doi:10.1021/jm061487a. PMID   17630725.
  3. ↑ Del Bello F, Mattioli L, Ghelfi F, Giannella M, Piergentili A, Quaglia W, et al. (November 2010). "Fruitful adrenergic α(2C)-agonism/α(2A)-antagonism combination to prevent and contrast morphine tolerance and dependence". Journal of Medicinal Chemistry. 53 (21): 7825–35. doi:10.1021/jm100977d. PMID   20925410.
  4. ↑ Hollister LE (17 July 1991). "AMA Drug Evaluations Annual 1991". JAMA: The Journal of the American Medical Association. 266 (3): 97. doi:10.1001/jama.1991.03470030126039.
  5. ↑ Commiskey S, Fan LW, Ho IK, Rockhold RW (June 2005). "Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors". Journal of Pharmacological Sciences. 98 (2): 109–16. doi: 10.1254/jphs.CRJ05001X . PMID   15942128.
  6. ↑ Schmidt WK, Tam SW, Shotzberger GS, Smith DH, Clark R, Vernier VG (February 1985). "Nalbuphine". Drug and Alcohol Dependence. 14 (3–4): 339–62. doi:10.1016/0376-8716(85)90066-3. PMID   2986929.
  7. ↑ Benson GJ, Tranquilli WJ (March 1992). "Advantages and guidelines for using opioid agonist-antagonist analgesics". The Veterinary Clinics of North America. Small Animal Practice. 22 (2): 363–5. doi:10.1016/S0195-5616(92)50637-4. PMID   1585578.
  8. ↑ Lasagna L (December 1987). "Benefit-risk ratio of agonist-antagonist analgesics". Drug and Alcohol Dependence. 20 (4): 385–93. doi: 10.1111/j.1360-0443.1989.tb00595.x . PMID   2894291.
  9. ↑ Dietis N, Guerrini R, Calo G, Salvadori S, Rowbotham DJ, Lambert DG (July 2009). "Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile". British Journal of Anaesthesia. 103 (1): 38–49. doi: 10.1093/bja/aep129 . PMID   19474215.
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