ABSTRACT
Development of SAR in a 5-aryl-3-acylpyridinyl-pyrazoles and 1-aryl-4-acylpyridinyl imidazoles series of mGlu5 receptor negative allosteric modulators (mGluR5 NAMs) using a functional cell-based assay is described in this Letter. Analysis of the Ligand-lipophilic efficiency (LipE) of compounds provided new insight for the design of potent mGluR5 negative allosteric modulators with anti-depressant activities.
Subject(s)
Amides/pharmacology , Drug Discovery , Imidazoles/pharmacology , Pyrazoles/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Allosteric Regulation/drug effects , Amides/chemical synthesis , Amides/chemistry , Animals , Binding Sites/drug effects , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Ligands , Mice , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Rats , Receptor, Metabotropic Glutamate 5 , Structure-Activity RelationshipABSTRACT
In this study, we determined mode of action of a novel carbamoyloxy arylalkanoyl arylpiperazine compound (SKL-NP) on hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents (I(h)) that plays important roles in neuropathic pain. In small or medium-sized dorsal root ganglion (DRG) neurons (<40 µm in diameter) exhibiting tonic firing and prominent I(h), SKL-NP inhibited I(h) and spike firings in a concentration dependent manner (IC(50)=7.85 µM). SKL-NP-induced inhibition of I(h) was blocked by pretreatment of pertussis toxin (PTX) and N-ethylmaleimide (NEM) as well as 8-Br-cAMP, a membrane permeable cAMP analogue. These results suggest that SKL-NP modulates I(h) in indirect manner by the activation of a Gi-protein coupled receptor that decreases intracellular cAMP concentration. Taken together, SKL-NP has the inhibitory effect on HCN channel currents (I(h)) in DRG neurons of rats.
ABSTRACT
A series of carbamic acid 1-phenyl-3-(4-phenyl-piperazine-1-yl)-propyl ester derivatives were synthesized through discovery strategies for balancing target-based in vitro screening and phenotypic in vivo screening. All the newly synthesized compounds were screened for their analgesic activities and compared with standard drug morphine. Among them, compound 44r, a potent analgesic agent that has favorable pharmacokinetic properties in rats and most importantly, has a wide safety margin. We demonstrated with in vitro and in vivo functional assays that its analgesic activity might be through 5-HT(2A) antagonism to some extent. Hence, it is concluded that there is ample scope for further study in developing compound 44r as a good lead candidate for an analgesic agent.
Subject(s)
Analgesics/chemical synthesis , Carbamates/chemical synthesis , Pain/drug therapy , Piperazines/chemical synthesis , Serotonin Antagonists/chemical synthesis , Analgesics/pharmacology , Animals , Carbamates/pharmacology , Esters , Mice , Molecular Structure , Morphine/pharmacology , Pain Measurement , Piperazines/pharmacology , Rats , Receptors, Serotonin, 5-HT2/metabolism , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
In this study we hypothesized that the residents in the disaster-exposed group would experience higher levels of stress, anxiety, depression and post-traumatic stress disorder compared to those in the non-disaster group. Furthermore, this would result in an increased need for health-related welfare in the disaster-exposed group. Our data supports both hypotheses, and these research findings are consistent with a growing body of research that supports such a conclusion.
