ABSTRACT
The affinity of the Ca(2+) ion for a set of substituted carbonyl ligands was analyzed with both the DFT (B3LYP/6-31+G(d)) and semi-empirical (PM6) methods. Two types of ligands were studied: a set of monosubstituted [O=CH(R)] and a set of disubstituted ligands [O=C(R)(2)] (R=H, F, Cl, Br, OH, OCH(3), CH(3), CN, NH(2) and NO(2)), with R either directly bound to the carbonyl carbon atom or to the para position of a phenyl ring. The interaction energy was calculated to quantify the affinity of the Ca(2+) cation for the ligands. Geometric and electronic parameters were correlated with the intensity of the metal-ligand interaction. The electronic nature of the substituent is the main parameter that determines the interaction energy. Donor groups make the interaction energy more negative (stabilizing the complex formed), while acceptor groups make the interaction energy less negative (destabilizing the complex formed).
Subject(s)
Calcium/chemistry , Carbon/chemistry , Metals, Alkaline Earth/chemistry , Organometallic Compounds/chemistry , Cations/chemistry , Computer Simulation , Hydrogen Bonding , Ligands , Models, Chemical , Molecular Structure , Water/chemistryABSTRACT
Our previous study described the synthesis of 4-amine derivatives of 10,11-dihydro-5H-dibenzo-alkylamine-cycloheptane, 4-amine (3-N,N-dimethylpropylamine)-10,11-dihydro-5H-dibenzo[a,d] cycloheptane-5-one (ADDCH1), and 1,2,3,4,8,9-hexahydro-dibenzocycloheptane[4,4a,5-ef]1,4-diazepin (ADDCH2), and the characterization of their antidepressant-like effect in the forced swimming test in mice. This study investigated the involvement of monoaminergic pathways in the antidepressant-like effect of these compounds in mice evaluated in the tail suspension test (TST), another animal model to screen antidepressant drugs. Our results show that the immobility time in the TST was significantly reduced by ADDCH1 (15 to 50 mg/kg, i.p.) or ADDCH2 (30 and 50 mg/kg, i.p.). The antidepressant-like effect of ADDCH1 (30 mg/kg, i.p.) in the TST was prevented by pre-treatment of mice with methysergide (2 mg/kg, i.p.), a non-selective serotonin receptor antagonist, p-chlorophenylalanine methylester (pCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis, prazosin (62.5 microg/kg, i.p.), an alpha1-adrenoceptor antagonist, or yohimbine (1 mg/kg, i.p.), an alpha2-adrenoceptor antagonist. In contrast, the antidepressant-like effect of ADDCH2 was antagonized only by yohimbine (1 mg/kg) or haloperidol (50 microg/kg, i.p.), a dopamine D2/D3/D4 receptor antagonist, and was not affected by methysergide, pCPA or prazosin. Altogether, the present results strongly suggest the differential involvement of monoaminergic systems, serotonin/noradrenaline (ADDCH1) and noradrenaline/dopamine (ADDCH2) pathways, respectively, in the antidepressant-like effect of dibenzosuberone compounds.
Subject(s)
Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Biogenic Monoamines/pharmacology , Cycloheptanes/pharmacology , Depressive Disorder/drug therapy , Disease Models, Animal , Hindlimb Suspension/physiology , Immobility Response, Tonic/drug effects , Animals , Antidepressive Agents/therapeutic use , Biogenic Monoamines/physiology , Cycloheptanes/therapeutic use , Haloperidol , Male , Mice , Motor Activity/drug effectsABSTRACT
This study investigated the antidepressant-like effect of 4-amine derivatives of 10,11-dihydro-5H-dibenzo-alkylamine-cycloheptane, 4-amine (3-N,N-dimethylpropylamine)-10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5-one (ADDCH1) and 1,2,3,4,8,9-hexahydro-dibenzocyclohepta[4,4a,5-ef]1,4-diazepin (ADDCH2), in a validated experimental model of depression, the forced swimming test (FST) in mice. Female adult mice were sub-chronically (three doses in 24 h) or repeatedly (once a day for 10 days) treated with either of the compounds and evaluated in the FST. The sub-chronic treatment promoted a dose-dependent reduction in the immobility time in the FST with the doses of 50 mg/kg (ADDCH1) and 30 mg/kg (ADDCH2) ip being the most effective (33% and 37% of reduction, respectively). A similar profile of action was observed in the animals repeatedly treated with ADDCH1 50 mg/kg or ADDCH2 30 mg/kg ip (for 10 days) and there was no sign of motor impairment or locomotor activation as evaluated in the rota-rod and open-field tests, respectively. These findings suggest that these amine derivatives of the system dibenzocycloheptane have an antidepressant-like action which could be of clinical interest and, therefore, deserves further investigation. In addition, putative underlying mechanisms of action are discussed.
Subject(s)
Amines , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Cycloheptanes , Depression/drug therapy , Exercise Test , Animals , Disease Models, Animal , Female , Mice , Motor Activity/drug effects , SwimmingABSTRACT
In this work, we performed the design, synthesis, and the structure-activity relationship studies of 13 new derivatives of thieno[2,3-b]pyridine. These derivatives were prepared in high yields (96-70%) and their structures were elucidated by IR, (1)H, (13)C NMR, and MS. The biological results showed some derivatives as antiparasitic agents against Giardia lamblia. Computational analysis of HOMO and LUMO energy, HOMO orbital coefficient distribution, electrostatic potential map, dipole moment, and density HOMO was performed to gain insight into the SAR aspects. This study pointed the p-methoxy substituted derivative as a leading compound for the development of new microbicidal medicines based on thieno[2,3-b]pyridine analogs.