ABSTRACT
Prescription opioids are a mainstay in the treatment of acute moderate to severe pain. However, chronic use leads to a host of adverse consequences including tolerance and opioid-induced hyperalgesia (OIH), leading to more complex treatment regimens and diminished patient compliance. Patients with OIH paradoxically experience exaggerated nociceptive responses instead of pain reduction after chronic opioid usage. The development of OIH and tolerance tend to occur simultaneously and, thus, present a challenge when studying the molecular mechanisms driving each phenomenon. We tested the hypothesis that a G protein-biased µ-opioid peptide receptor (MOPR) agonist would not induce symptoms of OIH, such as mechanical allodynia, following chronic administration. We observed that the development of opioid-induced mechanical allodynia (OIMA), a model of OIH, was absent in ß-arrestin1-/- and ß-arrestin2-/- mice in response to chronic administration of conventional opioids such as morphine, oxycodone and fentanyl, whereas tolerance developed independent of OIMA. In agreement with the ß-arrestin knockout mouse studies, chronic administration of TRV0109101, a G protein-biased MOPR ligand and structural analog of oliceridine, did not promote the development of OIMA but did result in drug tolerance. Interestingly, following induction of OIMA by morphine or fentanyl, TRV0109101 was able to rapidly reverse allodynia. These observations establish a role for ß-arrestins in the development of OIH, independent of tolerance, and suggest that the use of G protein-biased MOPR ligands, such as oliceridine and TRV0109101, may be an effective therapeutic avenue for managing chronic pain with reduced propensity for opioid-induced hyperalgesia.
Subject(s)
Analgesics, Opioid/administration & dosage , GTP-Binding Proteins/agonists , Hyperalgesia/drug therapy , Pain Measurement/drug effects , Receptors, Opioid, mu/agonists , Animals , Dose-Response Relationship, Drug , Drug Administration Schedule , GTP-Binding Proteins/physiology , HEK293 Cells , Humans , Hyperalgesia/pathology , Male , Mice , Mice, Inbred C57BL , Pain Measurement/methods , Receptors, Opioid, mu/physiologyABSTRACT
The concept of "ligand bias" at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical µ opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in ß-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased µ opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased µ opioid receptor agonist, TRV130 ((R)-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain.
Subject(s)
Acute Pain/drug therapy , Analgesics/pharmacology , Drug Discovery/methods , Receptors, Opioid, mu/agonists , Spiro Compounds/pharmacology , Thiophenes/pharmacology , Acute Pain/pathology , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Disease Models, Animal , GTP-Binding Proteins/metabolism , HEK293 Cells , Humans , Mice , Models, Chemical , Molecular Structure , Rats , Receptors, Opioid, mu/metabolism , Severity of Illness Index , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistryABSTRACT
The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in ß-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the µ-opioid receptor (MOR) to G proteins, but not ß-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel MOR G protein-biased ligand. In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less ß-arrestin recruitment and receptor internalization. In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. TRV130 successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology. These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain.
Subject(s)
Analgesics/pharmacology , GTP-Binding Proteins/metabolism , Gastrointestinal Tract/drug effects , Morphine/pharmacology , Receptors, Opioid, mu/metabolism , Respiratory System/drug effects , Animals , Arrestins/metabolism , Cell Line , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/drug therapy , Gastrointestinal Diseases/metabolism , HEK293 Cells , Humans , Ligands , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/metabolism , Respiratory Tract Diseases/chemically induced , Respiratory Tract Diseases/drug therapy , Respiratory Tract Diseases/metabolism , Signal Transduction/drug effects , beta-Arrestin 2 , beta-ArrestinsABSTRACT
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Subject(s)
Aniline Compounds/chemistry , Benzamides/chemistry , Receptor, Cannabinoid, CB2/agonists , Sulfonamides/chemistry , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacokinetics , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Pain/drug therapy , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB2 ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB2 agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.
Subject(s)
Aminopyridines/chemistry , Morpholines/chemistry , Pyridines/chemistry , Receptor, Cannabinoid, CB2/agonists , Administration, Oral , Aminopyridines/chemical synthesis , Aminopyridines/pharmacology , Animals , Dogs , Humans , Male , Microsomes, Liver , Morpholines/chemical synthesis , Morpholines/pharmacology , Pain/drug therapy , Protein Binding , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB(2) agonists. Selective CB(2) agonist 31 (K(i)=2.7; CB(1)/CB(2)=190) displayed robust activity in a rodent model of postoperative pain.
Subject(s)
Anti-Inflammatory Agents/chemistry , Benzamides/chemistry , Receptor, Cannabinoid, CB2/agonists , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , CHO Cells , Cell Line , Cricetinae , Cricetulus , Drug Discovery , Humans , Pain, Postoperative/drug therapy , Rats , Receptor, Cannabinoid, CB2/metabolism , Stereoisomerism , Structure-Activity Relationship , TransfectionABSTRACT
Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
Subject(s)
Analgesics/pharmacology , Analgesics/therapeutic use , Benzamides/pharmacology , Benzamides/therapeutic use , Benzopyrans/pharmacology , Benzopyrans/therapeutic use , Pain/drug therapy , Receptors, Opioid, delta/agonists , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use , Analgesics/administration & dosage , Analgesics/chemistry , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Benzopyrans/administration & dosage , Benzopyrans/chemistry , CHO Cells , Clinical Trials as Topic , Cricetinae , Cricetulus , Crystallography, X-Ray , Cytochrome P-450 CYP2D6 Inhibitors , Dogs , Dose-Response Relationship, Drug , Drug Discovery , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Hyperalgesia/drug therapy , Male , Rats , Rats, Sprague-Dawley , Spiro Compounds/administration & dosage , Spiro Compounds/chemistryABSTRACT
Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.
Subject(s)
Benzamides/pharmacology , Receptor, Cannabinoid, CB2/drug effects , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Benzamides/therapeutic use , Pain/drug therapy , RodentiaABSTRACT
Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.
Subject(s)
Analgesics/administration & dosage , Benzamides/administration & dosage , Benzopyrans/administration & dosage , Pain/drug therapy , Receptors, Opioid, delta/agonists , Administration, Oral , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Benzamides/chemical synthesis , Benzamides/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Biological Availability , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug-Related Side Effects and Adverse Reactions , Ether-A-Go-Go Potassium Channels/drug effects , Humans , Maximum Tolerated Dose , Mice , Molecular Structure , Motor Activity/drug effects , Pain Measurement/drug effects , Rats , Toxicity TestsABSTRACT
Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB(2) receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB(2) receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.
Subject(s)
Benzamides/therapeutic use , Neuralgia/drug therapy , Receptor, Cannabinoid, CB2/metabolism , Sulfonamides/therapeutic use , Animals , Benzamides/chemical synthesis , Benzamides/pharmacology , Binding Sites , Dose-Response Relationship, Drug , Ligands , Mice , Models, Animal , Models, Chemical , Pain Measurement/drug effects , Rats , Receptor, Cannabinoid, CB2/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
A novel series of malonamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists.
Subject(s)
Chemistry, Pharmaceutical/methods , Malonates/chemical synthesis , Malonates/pharmacology , Receptors, Opioid, kappa/antagonists & inhibitors , Cytochrome P-450 CYP2D6/chemistry , Drug Design , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Kinetics , Malonates/chemistry , Models, Chemical , Molecular ConformationABSTRACT
Nitric oxide generated by the nitric oxide synthase (NOS) isoforms contributes to pain processing. The selective inhibition of iNOS might represent a novel, therapeutic target for the development of antinociceptive compounds. However, few isoform-selective inhibitors of NOS have been developed. The present experiments examined the anti-inflammatory and antinociceptive activity of a selective inducible nitric oxide (iNOS) inhibitor, AR-C102222, on arachidonic acid-induced ear inflammation, Freund's complete adjuvant (FCA)-induced hyperalgesia, acetic acid-induced writhing, and tactile allodynia produced by L5 spinal nerve ligation (L5 SNL) or hindpaw incision (INC). AR-C102222 at a dose of 100mg/kg p.o., significantly reduced inflammation produced by the application of arachidonic acid to the ear, attenuated FCA-induced mechanical hyperalgesia, and attenuated acetic acid-induced writhing. In the L5 SNL and INC surgical procedures, tactile allodynia produced by both procedures was significantly reduced by 30mg/kg i.p. of AR-C102222. These data demonstrate that the selective inhibition of iNOS produces antinociception in different models of pain and suggest that the iNOS-NO system plays a role in pain processing.
Subject(s)
Hyperalgesia/drug therapy , Inflammation/drug therapy , Mononeuropathies/drug therapy , Nitric Oxide Synthase/antagonists & inhibitors , Pain/drug therapy , Quinazolines/therapeutic use , Animals , Disease Models, Animal , Inflammation/complications , Male , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Mononeuropathies/complications , Pain/etiology , Rats , Rats, Sprague-DawleyABSTRACT
The identification of peripherally expressed CB2 receptors and reports that the selective activation of cannabinoid CB2 receptors produces antinociception without traditional cannabinergic side effects suggests that selective cannabinoid CB2 receptor agonists might be useful in the management of pain. In a rat hindpaw incision model, we examined the antiallodynic activity of the selective cannabinoid CB2 receptor agonists AM1241 (3-30 mg/kg i.p.), GW405833 (3-30 mg/kg i.p.), and HU-308 (0.3-30 mg/kg i.p.). The rank order for efficacy in the hindpaw incision model following a dose of 10 mg/kg, i.p. was AM1241 > GW405833 = HU-308, and the selective cannabinoid CB2 receptor antagonist, SR144528, reversed the antiallodynic effect of HU-308. Together, these data suggest that selective cannabinoid CB2 receptor agonists might represent a new class of postoperative analgesics.
Subject(s)
Hindlimb/surgery , Pain, Postoperative/prevention & control , Receptor, Cannabinoid, CB2/agonists , Animals , Camphanes/administration & dosage , Camphanes/therapeutic use , Cannabinoids/administration & dosage , Cannabinoids/therapeutic use , Drug Administration Schedule , Foot Injuries/surgery , Indoles/administration & dosage , Indoles/therapeutic use , Male , Models, Animal , Morpholines/administration & dosage , Morpholines/therapeutic use , Pain/prevention & control , Pain Measurement/methods , Pain, Postoperative/physiopathology , Pyrazoles/administration & dosage , Pyrazoles/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Time FactorsABSTRACT
A series of 3-substituted analogs (3) of the parent kappa agonist, 1, were prepared to limit access to the central nervous system. With the exception of compound 3j, all other compounds bound to the human kappa opioid receptor with high affinity (K(i)=0.31-9.5 nM) and were selective for kappa over mu and delta opioid receptors. Compounds 3c, d, and 3g-i produced potent antinociceptive activity in the rat formalin assay (i.paw) and the mouse acetic acid-induced writhing assay (s.c.), with weak activity in the mouse platform sedation test. The peripheral restriction indices of 3c, d, 3g, and 3i were improved 2- to 7-fold compared to the parent compound 1, and these compounds were approximately 2- to 5-fold more potent than the peripheral kappa agonist ICI 204448.
Subject(s)
Analgesics/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Opioid, kappa/agonists , Amides/chemical synthesis , Amides/pharmacology , Analgesics/pharmacology , Animals , Central Nervous System/metabolism , Drug Evaluation, Preclinical , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Pain/drug therapy , Pain Threshold/drug effects , Pyrrolidines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A new class of kappa-opioid receptor agonists is described. The design of these agents was based upon energy minimization and structural overlay studies of the generic azepin-2-one structure 3 with the crystal structure of arylacetamide kappa agonist 1, ICI 199441. The most active compound identified was ligand 4a (K(i)=0.34 nM), which demonstrated potent antinociceptive activity after oral administration in rodents.