ABSTRACT
Several analogs of gigantol (1) were synthesized to evaluate their effect on the complexes Ca(2+)-calmodulin (CaM) and Ca(2+)-CaM-CaM sensitive phosphodiesterase 1 (PDE1). The compounds belong to four structural groups including, 1,2-diphenylethanes (2-11), diphenylmethanes (13-15), 1,3-diphenylpropenones (16-18), and 1,3-diphenylpropanes (20-22). In vitro enzymatic studies showed that all compounds except 11 inhibited the complex Ca(2+)-CaM-PDE1 with IC(50) values ranging from 9 to 146 µM. On the other hand, all analogs but 11, 12 and 15 quenched the extrinsic fluorescence of the CaM biosensor hCaM-M124C-mBBr to different extent, then revealing different affinities to CaM; their affinity constants (K(m)) values were in the range of 3-80 µM. Molecular modeling studies indicated that all these compounds bound to CaM at the same site that the classical inhibitors trifluoperazine (TFP) and chlorpromazine (CPZ). Some of these analogs could be worthy candidates for developing new anti-tumor, local anesthetics, antidepressants, antipsychotic, or smooth muscle relaxant drugs, with anti-CaM properties due to their good affinity to CaM and the straightforwardness of their synthesis. In addition they could be valuable tools for the study of Ca(2+)-CaM functions.
Subject(s)
Bibenzyls/chemical synthesis , Biphenyl Compounds/chemical synthesis , Calmodulin/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 1/antagonists & inhibitors , Guaiacol/analogs & derivatives , Anesthetics, Local/chemical synthesis , Anesthetics, Local/chemistry , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Bibenzyls/chemistry , Biosensing Techniques , Biphenyl Compounds/chemistry , Calmodulin/chemistry , Chlorpromazine/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 1/chemistry , Guaiacol/chemical synthesis , Guaiacol/chemistry , Humans , Molecular Docking Simulation , Parasympatholytics/chemical synthesis , Parasympatholytics/chemistry , Protein Binding , Trifluoperazine/chemistryABSTRACT
The present structure-activity relationship (SAR) study focused on chemical modifications of the structure of the local anesthetic lidocaine, and indicated analogues having reduced anesthetic potency, but with superior potency relative to the prototype in preventing anaphylactic or histamine-evoked ileum contraction. From the SAR analysis, 2-(diethylamino)-N-(trifluoromethyl-phenyl) and 2-(diethylamino)-N-(dimethyl-phenyl) acetamides were selected as the most promising compounds. New insights into the applicability of non-anesthetic lidocaine derivatives as templates in drug discovery for allergic syndromes are provided.