ABSTRACT
Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
Subject(s)
Amides/chemistry , Antihypertensive Agents/chemistry , Cyclohexanols/chemistry , Isoxazoles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Cyclohexanols/chemical synthesis , Cyclohexanols/pharmacokinetics , Hyperthermia, Induced , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.
Subject(s)
Amides/chemistry , Indoles/chemistry , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Dogs , Drug Evaluation, Preclinical , Indoles/chemical synthesis , Indoles/pharmacokinetics , Male , Mice , Models, Molecular , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/metabolism , Structure-Activity RelationshipABSTRACT
A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement of the benzimidazol-2-one moiety was explored. Compound 51 was found to be a high affinity, potent NOP receptor agonist with reduced affinity for the hERG channel.
Subject(s)
Benzimidazoles/chemistry , Narcotic Antagonists/chemistry , Piperidines/chemistry , Animals , Cricetinae , Receptors, Opioid/metabolism , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
The N-3 position of a series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues was optimised using the predictive power of a CoMFA model. The model was used to prioritise compounds for synthesis culminating in the triazole (+)-24. (+)-24 was found to be a high affinity, potent NOP agonist and demonstrated both antinociceptive and antiallodynic effects when administered iv to rodents.
Subject(s)
Benzimidazoles/chemistry , Models, Molecular , Receptors, Opioid/agonists , Analgesics/chemistry , Animals , Benzimidazoles/pharmacology , Hypnotics and Sedatives/chemistry , Rodentia , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
BACKGROUND: Agonists at the opioid receptor-like receptor 1 (ORL1) induce motor impairment, sedation, and loss of righting reflex (LRR) in rodents. This receptor may provide a novel target in the field of anesthesia. METHODS: We examined the hypnotic, electroencephalographic (EEG), and antinociceptive effects of two IV administered nonpeptide ORL1 agonists, (Ro 65-6570 and Org 26383), using LRR in mice and rats, percent EEG burst suppression in rats, and formalin paw test in mice. RESULTS: In mice, Ro 65-6570 and Org 26383 produced LRR (hypnotic dose 0.6 and 3.7 micromol/kg for Ro 65-6570 and Org 26383, respectively). Naloxone had no significant effect on sleep times produced by both compounds. In rats, Ro 65-6570 (0.6-2.4 micromol/kg) and Org 26383 (4-8 micromol/kg) produced LRR and burst suppression activity in the EEG. Both sleep times and burst suppression activity were significantly reduced with a selective ORL1 antagonist. In mice, dose-dependent inhibition of formalin-induced nociceptive behaviors occurred (Phase 1 ED50 0.4 and 1.8 micromol/kg and Phase 2 ED50 0.4 and 4.2 micromol/kg for Ro 65-6570 and Org 26383, respectively). CONCLUSIONS: These results show that Ro 65-6570 and Org 26383 (probably via the ORL1 receptor) behave as IV hypnotics and analgesics in mice and rats, and that the hypnotic and antinociceptive doses are similar.
Subject(s)
Electroencephalography , Imidazoles/pharmacology , Receptors, Opioid/agonists , Spiro Compounds/pharmacology , Animals , Electroencephalography/drug effects , Humans , Imidazoles/administration & dosage , Injections, Intravenous , Male , Mice , Mice, Inbred ICR , Models, Animal , Naloxone/administration & dosage , Naloxone/pharmacology , Rats , Rats, Wistar , Spiro Compounds/administration & dosage , Nociceptin ReceptorABSTRACT
A series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues have been discovered as novel NOP receptor agonists. Structure-activity relationships have been explored via N-3 substitution of the benzimidazol-2-one with a range of functionality. The N-methyl acetamide derivative (+)-7f was found to be a high-affinity, potent NOP agonist with greater than 100-fold selectivity over the MOP receptor. Furthermore (+)-7f was shown to be both antinociceptive and sedative when administered iv to rodents.
Subject(s)
Analgesics/chemical synthesis , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Hypnotics and Sedatives/chemical synthesis , Receptors, Opioid/agonists , Animals , Rodentia , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
The binding of rocuronium bromide to 6-perdeoxy-6-per(4-carboxyphenyl)thio-gamma-cyclodextrin sodium salt, displays biphasic behaviour characteristic of the formation of a binary and 2 : 1 ternary guest-host complex in aqueous solution. Thermodynamic and structural data on this sequential complexation process can be rationalised within a single model involving switching of the conformational equilibria of both the rocuronium bromide and cyclodextrin molecules. Isothermal titration calorimetry (ITC), NMR and fluorescence experiments in solution, together with X-ray crystallography and molecular modelling, suggest that in order to induce encapsulation both rocuronium bromide and the modified cyclodextrin undergo conformational changes. Ring A of rocuronium bromide 'switches' from the more sterically encumbered chair to the sterically less demanding twist-boat, whilst the modified cyclodextrin "opens" its cavity to allow the steroid to enter. The recognition and mutual induced fit between cyclodextrin and steroid represents a classic example of dynamic host-guest chemistry.
Subject(s)
Androstanols/chemistry , Cyclodextrins/chemistry , Neuromuscular Blocking Agents/chemistry , Calorimetry , Crystallography , Magnetic Resonance Spectroscopy , Rocuronium , Spectrometry, Fluorescence , Spectrophotometry, UltravioletABSTRACT
A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified.
Subject(s)
Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Opioid/agonists , Animals , CHO Cells , Cricetinae , Cyclic AMP/biosynthesis , Drug Design , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Male , Mice , Structure-Activity Relationship , Transfection , Vas Deferens , Nociceptin ReceptorSubject(s)
Androstanols/chemistry , Cyclodextrins/chemistry , Neuromuscular Blockade , Neuromuscular Nondepolarizing Agents/chemistry , gamma-Cyclodextrins , Androstanols/pharmacology , Animals , Crystallography, X-Ray , Cyclodextrins/pharmacology , Diaphragm/drug effects , Diaphragm/innervation , In Vitro Techniques , Macaca mulatta , Mice , Models, Molecular , Muscle Contraction/drug effects , Neuromuscular Nondepolarizing Agents/pharmacology , Rocuronium , SugammadexABSTRACT
A series benzylpiperidinium and benzylpyridinium quaternary salts have been synthesised and tested for inhibition of acetylcholinesterase and reversal of neuromuscular block induced by vecuronium. Several potent reversal agents have been identified and their haemodynamic effects measured.
Subject(s)
Acetylcholinesterase/drug effects , Cholinesterase Inhibitors/pharmacology , Indans/pharmacology , Neuromuscular Nondepolarizing Agents/antagonists & inhibitors , Piperidines/pharmacology , Vecuronium Bromide/antagonists & inhibitors , Cholinesterase Inhibitors/chemistry , Donepezil , Indans/chemistry , Piperidines/chemistryABSTRACT
A series of piperidinium and pyridinium agents containing a common structural fragment of 5,6-dimethoxybenzothiophene have been synthesised as water-soluble acetylcholinesterase inhibitors. Several compounds, for example 42 (AChE IC(50) 0.03 microM) have been found to reverse the neuromuscular blockade induced by vecuronium bromide in vitro and in vivo. Coupled with their high water solubility (up to 30-60 mg/mL), these compounds are potentially useful as intravenous reversal agents of neuromuscular blocking agents in surgical anaesthesia.
Subject(s)
Acetylcholinesterase/drug effects , Cholinesterase Inhibitors/pharmacology , Neuromuscular Nondepolarizing Agents/pharmacology , Piperidines/pharmacology , Pyridines/pharmacology , Vecuronium Bromide/antagonists & inhibitors , Animals , Cholinesterase Inhibitors/chemistry , Cricetinae , Diaphragm/drug effects , Neuromuscular Nondepolarizing Agents/chemistry , Piperidines/chemistry , Pyridines/chemistry , Solubility , WaterABSTRACT
A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.
Subject(s)
Androstanols/chemistry , Cyclodextrins/chemical synthesis , Neuromuscular Nondepolarizing Agents/chemical synthesis , gamma-Cyclodextrins , Animals , Crystallography, X-Ray , Cyclodextrins/chemistry , Cyclodextrins/pharmacology , Diaphragm/drug effects , Diaphragm/innervation , Drug Evaluation, Preclinical , Guinea Pigs , Hydrophobic and Hydrophilic Interactions , In Vitro Techniques , Magnetic Resonance Spectroscopy , Male , Mice , Models, Molecular , Neuromuscular Nondepolarizing Agents/chemistry , Rocuronium , Static Electricity , Structure-Activity Relationship , SugammadexABSTRACT
Although numerous reversal agents for neuromuscular block (NMB) have been known for some time, investigations on new approaches were initiated only recently. The different approaches used in an attempt to avoid the muscarinic side effects associated with the antagonists of NMB that are currently available are reviewed.