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1.
J Med Chem ; 66(4): 2964-2978, 2023 02 23.
Article in English | MEDLINE | ID: mdl-36749855

ABSTRACT

GPR88 is an orphan G protein-coupled receptor mainly expressed in the brain, whose endogenous ligand has not yet been identified. To elucidate GPR88 functions, our group has developed RTI-13951-33 (1b) as the first in vivo active GPR88 agonist, but its poor metabolic stability and moderate brain permeability remain to be further optimized. Here, we report the design, synthesis, and pharmacological characterization of a new series of RTI-13951-33 analogues with the aim of improving pharmacokinetic properties. As a result, we identified a highly potent GPR88 agonist RTI-122 (30a) (cAMP EC50 = 11 nM) with good metabolic stability (half-life of 5.8 h) and brain permeability (brain/plasma ratio of >1) in mice. Notably, RTI-122 was more effective than RTI-13951-33 in attenuating the binge-like alcohol drinking behavior in the drinking-in-the-dark paradigm. Collectively, our findings suggest that RTI-122 is a promising lead compound for drug discovery research of GPR88 agonists.


Subject(s)
Drug Design , Receptors, G-Protein-Coupled , Animals , Mice , Brain/metabolism , Receptors, G-Protein-Coupled/agonists , Drug Stability , Alcohol Drinking/drug therapy
2.
J Med Chem ; 64(12): 8806-8825, 2021 06 24.
Article in English | MEDLINE | ID: mdl-34101446

ABSTRACT

Loss of orexin-producing neurons results in narcolepsy with cataplexy, and orexin agonists have been shown to increase wakefulness and alleviate narcolepsy symptoms in animal models. Several OX2R agonists have been reported but with little or no activity at OX1R. We conducted structure-activity relationship studies on the OX2R agonist YNT-185 (2) and discovered dual agonists such as RTOXA-43 (40) with EC50's of 24 nM at both OX2R and OX1R. Computational modeling studies based on the agonist-bound OX2R cryogenic electron microscopy structures showed that 40 bound in the same binding pocket and interactions of the pyridylmethyl group of 40 with OX1R may have contributed to its high OX1R potency. Intraperitoneal injection of 40 increased time awake, decreased time asleep, and increased sleep/wake consolidation in 12-month old mice. This work provides a promising dual small molecule agonist and supports development of orexin agonists as potential treatments for orexin-deficient disorders such as narcolepsy.


Subject(s)
Orexin Receptors/agonists , Sleep/drug effects , Sulfonamides/pharmacology , Wakefulness/drug effects , Animals , CHO Cells , Cricetulus , Female , Male , Mice , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Orexin Receptors/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolism
3.
Br J Anaesth ; 125(4): 596-604, 2020 10.
Article in English | MEDLINE | ID: mdl-32819621

ABSTRACT

BACKGROUND: A novel G-protein signalling-biased mu opioid peptide (MOP) receptor agonist, PZM21, was recently developed with a distinct chemical structure. It is a potent Gi/o activator with minimal ß-arrestin-2 recruitment. Despite intriguing activity in rodent models, PZM21 function in non-human primates is unknown. The aim of this study was to investigate PZM21 actions after systemic or intrathecal administration in primates. METHODS: Antinociceptive, reinforcing, and pruritic effects of PZM21 were compared with those of the clinically used MOP receptor agonists oxycodone and morphine in assays of acute thermal nociception, capsaicin-induced thermal allodynia, itch scratching responses, and drug self-administration in gonadally intact, adult rhesus macaques (10 males, six females). RESULTS: After subcutaneous administration, PZM21 (1.0-6.0 mg kg-1) and oxycodone (0.1-0.6 mg kg-1) induced dose-dependent thermal antinociceptive effects (P<0.05); PZM21 was 10 times less potent than oxycodone. PZM21 exerted oxycodone-like reinforcing effects and strength as determined by two operant schedules of reinforcement in the intravenous drug self-administration assay. After intrathecal administration, PZM21 (0.03-0.3 mg) dose-dependently attenuated capsaicin-induced thermal allodynia (P<0.05). Although intrathecal PZM21 and morphine induced MOP receptor-mediated antiallodynic effects, both compounds induced robust, long-lasting itch scratching. CONCLUSIONS: PZM21 induced antinociceptive, reinforcing, and pruritic effects similar to clinically used MOP receptor agonists in primates. Although structure-based discovery of PZM21 identified a novel avenue for studying G-protein signalling-biased ligands, biasing an agonist towards G-protein signalling pathways did not determine or alter reinforcing (i.e. abuse potential) or pruritic effects of MOP receptor agonists in a translationally relevant non-human primate model.


Subject(s)
Analgesics/pharmacology , Pruritus/chemically induced , Receptors, Opioid, mu/agonists , Reinforcement, Psychology , Thiophenes/pharmacology , Urea/analogs & derivatives , Animals , Dose-Response Relationship, Drug , Female , Macaca mulatta , Male , Urea/pharmacology
4.
Brain Res ; 1731: 145922, 2020 03 15.
Article in English | MEDLINE | ID: mdl-30148984

ABSTRACT

The orexin system includes the neuropeptides orexin A and B and the cognate receptors of orexin-1 (OX1) and -2 (OX2) and has been indicated in a number of important physiological processes. It is generally accepted that the OX1 receptor is mainly involved in motivation and reward and the OX2 receptor in the modulation of sleep/wake cycle and energy homeostasis. A variety of OX1 selective antagonists (1-SORAs) have been disclosed in the literature and some of them have been evaluated as potential therapeutics for addiction treatment. In this review we summarize all OX1 antagonists reported thus far based on their core structure. Several dual orexin receptor antagonists (DORAs) and OX2 selective antagonist (2-SORAs) have also been recently evaluated in reward and addiction models. While DORAs may seem pharmacologically advantageous for alcohol addiction given the recent findings on the OX2 receptor in reward and alcohol consumption, 1-SORAs are the better options for other drugs of addiction such as cocaine due to the absence of the sedative effects inherently associated with dual antagonists.


Subject(s)
Brain/drug effects , Orexin Receptor Antagonists/administration & dosage , Substance-Related Disorders/drug therapy , Animals , Behavior, Addictive/drug therapy , Brain/physiology , Humans , Reward , Substance-Related Disorders/physiopathology
5.
European J Org Chem ; 2018(29): 4006-4012, 2018 Aug 07.
Article in English | MEDLINE | ID: mdl-32831629

ABSTRACT

PZM21 (1) was recently reported as a biased agonist of the mu-opioid receptor (MOR) with improved antinociceptive effects but reduced side effects than traditional opioid-based analgesics. The original synthesis of PZM21 with the desired (S,S) configuration required the separation of diastereomeric mixture in the final step using chiral HPLC. We have designed a concise synthesis of 1 in the enantiomeric pure form starting with commercially available L-alanine and via a chiral aziridine as a key intermediate. The final product 1 as the (S,S) diastereomer was obtained in 7 steps in 22.5% yield from L-alanine. This synthetic strategy could be readily applied to the development of PZM21 analogs at the thiophenyl position.

6.
ACS Chem Neurosci ; 9(3): 587-602, 2018 03 21.
Article in English | MEDLINE | ID: mdl-29129052

ABSTRACT

Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogues where the 7-position substituents known to favor OX1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies. Compound 44 with lower lipophilicity (clogP = 3.07) displayed excellent OX1 potency ( Ke = 5.7 nM) and selectivity (>1,760-fold over OX2) in calcium mobilization assays. In preliminary ADME studies, 44 showed excellent kinetic solubility (>200 µM), good CNS permeability ( Papp = 14.7 × 10-6 cm/sec in MDCK assay), and low drug efflux (efflux ratio = 3.3).


Subject(s)
Orexin Receptors/drug effects , Orexins/pharmacology , Permeability/drug effects , Tetrahydroisoquinolines/pharmacology , Animals , Hypothalamus/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Neuropeptides/metabolism , Orexin Receptor Antagonists/pharmacology , Receptors, G-Protein-Coupled/drug effects , Solubility
7.
Synthesis (Stuttg) ; 49(6): 1394-1400, 2017 Mar.
Article in English | MEDLINE | ID: mdl-31571700

ABSTRACT

SB612111 ((5S,7S)-7-{[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl}-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol) is a potent and selective antagonist of the nociception/orphanin FQ peptide (NOP) receptor. In the process of synthesizing cis-SB612111 to support ongoing animal studies, several key steps of the published syntheses in the patent literature proceeded in low yields in our hands, particularly with the route to the key intermediate piperidine 3, the reduction of amide 14, lactone 17 formation and the final reductive amination between 18 and 3 in the diastereoselective synthesis. We have thus explored various reaction conditions and successfully improved the yields for the necessary synthetic steps. We herein report our modified synthesis of SB612111 as the cis-diastereomers.

8.
Bioorg Med Chem ; 23(17): 5709-24, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-26216017

ABSTRACT

Selective antagonism of the orexin 1 (OX1) receptor has been proposed as a potential mechanism for treatment of drug addiction. We have previously reported studies on the structure-activity relationships of tetrahydroisoquinoline-based antagonists. In this report, we elucidated the respective role of the 6- and 7-substitutions by preparation of a series of either 6-substituted tetrahydroisoquinolines (with no 7-substituents) or vice versa. We found that 7-substituted tetrahydroisoquinolines showed potent antagonism of OX1, indicating that the 7-position is important for OX1 antagonism (10 c, Ke = 23.7 nM). While the 6-substituted analogs were generally inactive, several 6-amino compounds bearing ester groups showed reasonable potency (26 a, Ke = 427 nM). Further, we show evidence that suggests several compounds initially displaying insurmountable antagonism at the OX1 receptor are competitive antagonists with slow dissociation rates.


Subject(s)
Orexins/genetics , Tetrahydroisoquinolines/metabolism , Humans , Molecular Structure , Structure-Activity Relationship
9.
ACS Chem Neurosci ; 6(4): 599-614, 2015 Apr 15.
Article in English | MEDLINE | ID: mdl-25643283

ABSTRACT

Selective blockade of the orexin-1 receptor (OX1) has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain's reward system. We have recently reported a series of tetrahydroisoquinoline-based OX1 selective antagonists. Aimed at elucidating structure-activity relationship requirements in other regions of the molecule and further enhancing OX1 potency and selectivity, we have designed and synthesized a series of analogues bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX1 receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound 73 (RTIOX-251) with an apparent dissociation constant (Ke) of 16.1 nM at the OX1 receptor and >620-fold selectivity over the OX2 receptor. In vivo, compound 73 was shown to block the development of locomotor sensitization to cocaine in rats.


Subject(s)
Orexin Receptor Antagonists/chemistry , Orexin Receptor Antagonists/pharmacology , Tetrahydroisoquinolines/chemistry , Tetrahydroisoquinolines/pharmacology , Animals , CHO Cells , Calcium/metabolism , Cocaine/pharmacology , Cricetulus , Dopamine Uptake Inhibitors/pharmacology , Dose-Response Relationship, Drug , Humans , Locomotion/drug effects , Locomotion/physiology , Male , Molecular Structure , Orexin Receptor Antagonists/chemical synthesis , Orexin Receptors/chemistry , Orexin Receptors/genetics , Orexin Receptors/metabolism , Rats, Sprague-Dawley , Tetrahydroisoquinolines/chemical synthesis
10.
ACS Med Chem Lett ; 5(6): 634-8, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24944734

ABSTRACT

Cannabinoid CB1 and orexin OX1 receptors have been suggested to form heterodimers and oligomers. Aimed at studying these complexes, a series of bivalent CB1 and OX1 ligands combining SR141716 and ACT-078573 pharmacophores were designed, synthesized, and tested for activity against CB1 and OX1 individually and in cell lines that coexpress both receptors. Compound 20 showed a robust enhancement in potency at both receptors when coexpressed as compared to individually expressed, suggesting possible interaction with CB1-OX1 dimers. Bivalent ligands targeting CB1-OX1 receptor dimers could be potentially useful as a tool for further exploring the roles of such heterodimers in vitro and in vivo.

11.
J Med Chem ; 56(17): 6901-16, 2013 Sep 12.
Article in English | MEDLINE | ID: mdl-23941044

ABSTRACT

Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and a preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats.


Subject(s)
Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Tetrahydroisoquinolines/pharmacology , Animals , Cocaine/pharmacology , Orexin Receptors , Rats , Structure-Activity Relationship
12.
Bioorg Med Chem Lett ; 21(10): 2980-5, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21478014

ABSTRACT

As a part of our program to develop OX1-CB1 bivalent ligands, we required a better understanding of the basic structure-activity relationships (SARs) of orexin antagonists. A series of SB-334867 analogues were synthesized and evaluated in calcium mobilization assays. SAR results suggest that the 2-methylbenzoxazole moiety may be replaced with a disubstituted 4-aminophenyl group without loss of activity and an electron-deficient system is generally preferred at the 1,5-naphthyridine moiety for OX1 antagonist activity. In particular, substitution of larger potential linkers such as n-hexyl provided compound 33 with equivalent activity at the OX1 receptor compared to the lead compound SB-334867. These compounds should be of value in the development of ligands targeting the orexin-1 receptor and its potential heterodimers.


Subject(s)
Benzoxazoles/pharmacology , Receptors, G-Protein-Coupled/agonists , Receptors, Neuropeptide/agonists , Urea/analogs & derivatives , Urea/chemistry , Urea/pharmacology , Benzoxazoles/chemistry , Drug Delivery Systems , Ligands , Molecular Structure , Naphthyridines , Orexin Receptors , Protein Binding/drug effects , Structure-Activity Relationship
13.
Eur J Med Chem ; 43(6): 1123-51, 2008 Jun.
Article in English | MEDLINE | ID: mdl-17981367

ABSTRACT

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.


Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria/drug effects , Magnetic Resonance Spectroscopy , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Spectrometry, Mass, Electrospray Ionization
14.
Eur J Med Chem ; 42(11-12): 1334-57, 2007.
Article in English | MEDLINE | ID: mdl-17433505

ABSTRACT

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.


Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Eimeria/drug effects , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Biological Availability , Coccidiostats/chemistry , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Cyclic GMP-Dependent Protein Kinases/metabolism , Eimeria/physiology , Imidazoles/chemistry , Inhibitory Concentration 50 , Pyridines/chemistry
15.
Drug Dev Ind Pharm ; 28(2): 143-9, 2002.
Article in English | MEDLINE | ID: mdl-11926358

ABSTRACT

The chemical stability of a novel cysteine chloromethyl ketone derivative (HI-131) with anti-leukemic activity has been investigated in a microemulsion formulation. HI-131 degrades to two major products, most likely by undergoing oxidation and further reaction with another HI-131 molecule to form higher molecular weight oligomers of the original compound. The degradation kinetics of HI-131 have been studied as a function of pH, buffer composition, ionic strength, and temperature. Degradation follows pseudo-first-order kinetics and the temperature effect obeys the Arrhenius equation. The pH-rate profile demonstrates HI-131 is most stable at lower pH values, although there is no significant influence of ionic strength and buffer ions on the degradation rate. The chemical stability of a homologous series of chloromethyl and diazomethyl ketone derivatives of HI-131 has also been investigated in microemulsion. The relationship between the chain length of the derivatives and the stability is presented. Changing the chloro group to a bromo group resulted in an increase in degradation rate. Alterations to the group on the nitrogen were also investigated. The changes to the stability are discussed in terms of their mechanistic implications.


Subject(s)
Amino Acid Chloromethyl Ketones/chemistry , Antineoplastic Agents/chemistry , Cystine/chemistry , Diazomethane/analogs & derivatives , Diazomethane/chemistry , Ketones/chemistry , Cysteine/chemistry , Cystine/analogs & derivatives , Drug Stability , Emulsions , Hydrogen-Ion Concentration , Kinetics , Temperature
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