Relationship between Electronic Structure and Cytotoxic Activity of Dopamine and 3-Benzazepine Derivatives
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A structure-activity relationship of dopamine and3-benzazepine derivatives is discussed, using theoreticallycalculated results. In order to clearly divide dopamines and3-benzazepines into a strongly active and a weakly activegroup, the CC50, two different dipole moments (μESP-G and μESP-W) and heat of formation (ΔHf ) of dopamine [1-13]and 3-benzazepine derivatives [14-23] were separatelycalculated in two states of gas-phase and water-solution by theCOSMO/PM3 method. It was found that ten derivatives [1-3,9, 12-13 and 20-23] (CC50: 0.056 to 2.5 mM) showed thestrongest cytotoxic activity with small ΔΔHf values, whereasthirteen derivatives [4-8, 10-11, 14-19] (CC50: > 3.6 mM)showed the weakest cytotoxic activity with large ΔΔHf values.3-Benzazepines possess a wide range of interesting biologicalactivities such as reverse transcriptase inhibition, anantimicrobial effect, cytotoxic activity, adrenoreceptorantagonism, binding to the phencyclidine site of the Nmethyl-D-aspartate (NMDA) receptor and alteration oflipophilicity (1). The benzazepines also showed an inhibitoryeffect on the functions of natural killer (NK) cells includinggranular lymphocytes and monocytes (2). 3-Benzazepines[20, 21, 22] exhibited an antimicrobial effect, F'lac plasmidelimination activity and antibody-dependent cellularcytotoxicity (ADCC). Interestingly, one compound, [23],could inhibit the antiplasmid effect of promethazine (aphenothiazine derivative), when compared to the control(promethazine alone) on plasmid curing effect (3). Three 7,8-dihydroxy-3-benzazepines [20-22], having the ability togenerate radicals, were cytotoxic to the human promyeloticleukaemia HL-60 cells (4). Some 3-benzazepine derivativesshowed an antagonist activity at the peripheral postjunctionalα-2 adrenoreceptors (5). The unsubstituted 3-benzazepinehad a considerable affinity for the phencyclidine binding siteof the N-methyl-D-aspartate (NMDA) receptor (6). Thealteration of the lipophilicity of 3-benzazepines themselvesdid not affect their pharmacokinetics, however, thepharmacokinetics of secondary amines may differ from thetertiary amines (7). The quantum chemical calculations of3-benzazepines have been correlated to (a) the accessoryπ-binding site in a location complementary to a suitablyoriented aromatic ring, (b) the effects on D-1 and D-2 D-Areceptors, (c) the effects on the 2-phenyldopamine, (d) theexceptional D-1 agonist potency and (e) the D-2 agonistactivity, using the calculation parameters (8). The D-1 D-Abinding activity has been correlated with the calculatedtorsion angle of the biphenyl portion of these molecules.Then, a good D-1 dopamine binding has been observed whenthe aromatic rings approach coplanarity, which means that apoor binding occurs when the aromatic rings are orthogonal(9). The N-methyl 3-benzazepines retained the good D-2agonist potency, but the substitution of N-methyl groupsconverted the D-1 agonist activity to antagonist activity (10).Based on the above quantum-chemical calculationsand their association with the biological activities of3-benzazepines, the purpose of this paper was to reveal anyrelationship between a molecular orbital calculation with 3-benzazepine and dopamine derivatives.5p.
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