Abstract
A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed on a series of the 11H-dibenz[b,e]azepine and dibenz[b,f][1,4]oxazepine derivatives as potent agonists of the human TRPA1 receptor. The CoMFA and CoMSIA models resulting from a 21 molecule training set gave r2cv values of 0.631 and 0.542 and r2 values of 0.986 and 0.981, respectively. The statistically significant models were validated by a test set of five compounds with predictive r2pred. values of 0.967 and 0.981 for CoMFA and CoMSIA, respectively. A systemic external validation was also performed on the established models. The information obtained from 3D counter maps could facilitate the design of more potent human TRPA1 receptor agonists.
Highlights
The transient receptor potential ankyrin 1 (TRPA1) receptor is a member of the transient receptor potential (TRP) family of the cation-selection channel and the only mammalian member of the TRPA
The activation of TRPA1 by a diversity of chemical agents is widely accepted. It can be activated by many pungent chemicals, including methyl salicylate [3], isothiocyanates like allylisothiocyanate, the pungent compound in mustard oil (MO), wasabi, and horseradish [3], cinnamaldehyde [3], Δ9-tetrahydrocannabinol (Δ9-THC, the psychoactive compound in marijuana) [9], allicin and diallyl disulphide [10], acrolein [10], and the lacrimators 1-chloroacetophenone (CN), dibenz[b,f][1,4]oxazepine (CR) and 2-chlorobenzylidene malononitrile (CS) [11]
A data set of 21 diverse analogues was selected as a training set to derive the conventional comparative molecular fields analysis (CoMFA)
Summary
The transient receptor potential ankyrin 1 (TRPA1) receptor is a member of the transient receptor potential (TRP) family of the cation-selection channel and the only mammalian member of the TRPA subfamily [1,2]. It is expressed in the dorsal root ganglion, trigeminal ganglion (TG) neurons [3], and non-sensory tissue [4]. The activation of TRPA1 by a diversity of chemical agents is widely accepted. A series of compounds containing 11H-dibenz[b,e]azepines, and dibenz[b,f ][1,4]oxazepines that function as extremely potent activators of the human TRPA1 receptor activities were reported by literature [5]. The constructed models can help in understanding the structure-activity relationship of these compounds and may serve as a useful guide for the design of new agonists with much higher agonistic potencies
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