Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors
The complexation of 3-alkylcarbonyloxy-7-bromo-5-(2'-chloro)phenyl-1,2-dihydro-3Н-1,4-benzodiazepine-2-ones (R=Мe (1), R=t-Bu (2)) with the central benzodiazepine receptors (CBDR) at six temperatures within the range of 0-35°С has been studied by the radioligand analysis method. It has been fou...
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| Опубліковано в: : | Журнал органічної та фармацевтичної хімії |
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| Дата: | 2012 |
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| Мова: | English |
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Інститут органічної хімії НАН України
2012
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| Цитувати: | Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors / S.P. Smulsky, N.O. Burenkova, S.A. Andronati, V.I. Pavlovsky, P.G. Polishchuk, K.S. Andronati // Журнал органічної та фармацевтичної хімії. — 2012. — Т. 10, вип. 4(40). — С. 65-70. — Бібліогр.: 34 назв. — англ. |
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Smulsky, S.P. Burenkova, N.O. Andronati, S.A. Pavlovsky, V.I. Polishchuk, P.G. Andronati, K.S. 2013-03-07T18:47:58Z 2013-03-07T18:47:58Z 2012 Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors / S.P. Smulsky, N.O. Burenkova, S.A. Andronati, V.I. Pavlovsky, P.G. Polishchuk, K.S. Andronati // Журнал органічної та фармацевтичної хімії. — 2012. — Т. 10, вип. 4(40). — С. 65-70. — Бібліогр.: 34 назв. — англ. 0533-1153 https://nasplib.isofts.kiev.ua/handle/123456789/42067 547.892+ 544-971.62+ 615.31 The complexation of 3-alkylcarbonyloxy-7-bromo-5-(2'-chloro)phenyl-1,2-dihydro-3Н-1,4-benzodiazepine-2-ones (R=Мe (1), R=t-Bu (2)) with the central benzodiazepine receptors (CBDR) at six temperatures within the range of 0-35°С has been studied by the radioligand analysis method. It has been found that formation of the supramolecular complex of compound 1 with CBDR is endothermic with a rather great and unfavourable change of enthalpy (ΔН1° = +32,3 kJ/m%l), which is compensated by signifi cant change in entropy (ΔS1° = +266,7 J/(mol×К)). On the contrary, the binding of compound 2 to CBDR is exothermic (ΔН2° = -20,7 kJ/mol) and with a favourable entropy change (ΔS2° = +90,4 J/(mol×К)). The ester carbonyl groups in compounds 1 and 2 are also supposed to form different hydrogen bonds with the receptor. Методом радіолігандного аналізу вивчено комплексоутворення 3-алкілкарбонілокси-7-бром-5-(2'-хлор)феніл-1,2-дигідро-ЗН-1,4-бенздіазепін-2-онів (R=алкіл R=Me (1), R=t-Ви (2)) з центральними бенздіазепіновими рецепторами (ЦБДР) при шести температурах у інтервалі 0-35°С. Встановлено, що утворення супрамолекулярного комплексу сполуки 1 з ЦБДР ендотермічне з доволі великою та несприятливою зміною ентальпії ΔН1°=32,3 кДж/моль), яка компенсується значною зміною ентропії (ΔS1°=266,7Дж/(моль×К)). Зв'язування сполуки 2 з ЦБДР екзотермічне (ΔН2°=-20,7 кДж/моль) зі сприятливою зміною ентропії (ΔS2°=90,4 Дж/(моль×К)). Передбачається також, що естерні карбонільні групи у сполуках 1 і 2 утворюють різні водневі зв'язки з рецептором. Методом радиолигандного анализа изучено комплексообразование 3-алкилкарбонилокси-7-бром-5-(2'-хлор)фенил-1,2-дигидро-ЗН-1,4-бенздиазепин-2-онов R=Me (1), R=t-Bu (2)) с центральными бенздиазепиновыми рецепторами (ЦБДР) при шести температурах в интервале 0-35°С. Обнаружено, что образование супрамолекулярного комплекса соединения 1 с ЦБДР эндотермическое с довольно большим и неблагоприятным изменением энтальпии (ΔH1°=32,3 кДж/моль), которое компенсировано значительным изменением энтропии (ΔS1°=266,7 Дж/(моль×К)). Связывание соединения 2 с ЦБДР экзотермическое (ΔH2°=-20,7 кДж/моль) и с благоприятным изменением энтропии (ΔS2°=90,4 Дж/(моль×К)). Предполагается также, что сложноэфирные карбонильные группы в соединениях 1 и 2 образуют различные водородные связи с рецептором. en Інститут органічної хімії НАН України Журнал органічної та фармацевтичної хімії Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors Термодинаміка комплексоутворення естерів 3-гідрокси-7-бром-5-(2'-хлор)феніл-1,2-дигідро-3H-1,4-бензодіазепін-2-онів з центральними бенздіазепіновими рецепторами Термодинамика комплексообразования эфиров 3-гидрокси-7-бром-5-(2'-хлор) фенил-1,2-дигидро-3H-1,4-бензодиазепин-2-онов с центральными бенздиазепиновыми рецепторами Article published earlier |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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DSpace DC |
| title |
Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors |
| spellingShingle |
Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors Smulsky, S.P. Burenkova, N.O. Andronati, S.A. Pavlovsky, V.I. Polishchuk, P.G. Andronati, K.S. |
| title_short |
Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors |
| title_full |
Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors |
| title_fullStr |
Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors |
| title_full_unstemmed |
Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors |
| title_sort |
thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3h-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors |
| author |
Smulsky, S.P. Burenkova, N.O. Andronati, S.A. Pavlovsky, V.I. Polishchuk, P.G. Andronati, K.S. |
| author_facet |
Smulsky, S.P. Burenkova, N.O. Andronati, S.A. Pavlovsky, V.I. Polishchuk, P.G. Andronati, K.S. |
| publishDate |
2012 |
| language |
English |
| container_title |
Журнал органічної та фармацевтичної хімії |
| publisher |
Інститут органічної хімії НАН України |
| format |
Article |
| title_alt |
Термодинаміка комплексоутворення естерів 3-гідрокси-7-бром-5-(2'-хлор)феніл-1,2-дигідро-3H-1,4-бензодіазепін-2-онів з центральними бенздіазепіновими рецепторами Термодинамика комплексообразования эфиров 3-гидрокси-7-бром-5-(2'-хлор) фенил-1,2-дигидро-3H-1,4-бензодиазепин-2-онов с центральными бенздиазепиновыми рецепторами |
| description |
The complexation of 3-alkylcarbonyloxy-7-bromo-5-(2'-chloro)phenyl-1,2-dihydro-3Н-1,4-benzodiazepine-2-ones (R=Мe (1), R=t-Bu (2)) with the central benzodiazepine receptors (CBDR) at six temperatures within the range of 0-35°С has been studied by the radioligand analysis method. It has been found that formation of the supramolecular complex of compound 1 with CBDR is endothermic with a rather great and unfavourable change of enthalpy (ΔН1° = +32,3 kJ/m%l), which is compensated by signifi cant change in entropy (ΔS1° = +266,7 J/(mol×К)). On the contrary, the binding of compound 2 to CBDR is exothermic (ΔН2° = -20,7 kJ/mol) and with a favourable entropy change (ΔS2° = +90,4 J/(mol×К)). The ester carbonyl groups in compounds 1 and 2 are also supposed to form different hydrogen bonds with the receptor.
Методом радіолігандного аналізу вивчено комплексоутворення 3-алкілкарбонілокси-7-бром-5-(2'-хлор)феніл-1,2-дигідро-ЗН-1,4-бенздіазепін-2-онів (R=алкіл R=Me (1), R=t-Ви (2)) з центральними бенздіазепіновими рецепторами (ЦБДР) при шести температурах у інтервалі 0-35°С. Встановлено, що утворення супрамолекулярного комплексу сполуки 1 з ЦБДР ендотермічне з доволі великою та несприятливою зміною ентальпії ΔН1°=32,3 кДж/моль), яка компенсується значною зміною ентропії (ΔS1°=266,7Дж/(моль×К)). Зв'язування сполуки 2 з ЦБДР екзотермічне (ΔН2°=-20,7 кДж/моль) зі сприятливою зміною ентропії (ΔS2°=90,4 Дж/(моль×К)). Передбачається також, що естерні карбонільні групи у сполуках 1 і 2 утворюють різні водневі зв'язки з рецептором.
Методом радиолигандного анализа изучено комплексообразование 3-алкилкарбонилокси-7-бром-5-(2'-хлор)фенил-1,2-дигидро-ЗН-1,4-бенздиазепин-2-онов R=Me (1), R=t-Bu (2)) с центральными бенздиазепиновыми рецепторами (ЦБДР) при шести температурах в интервале 0-35°С. Обнаружено, что образование супрамолекулярного комплекса соединения 1 с ЦБДР эндотермическое с довольно большим и неблагоприятным изменением энтальпии (ΔH1°=32,3 кДж/моль), которое компенсировано значительным изменением энтропии (ΔS1°=266,7 Дж/(моль×К)). Связывание соединения 2 с ЦБДР экзотермическое (ΔH2°=-20,7 кДж/моль) и с благоприятным изменением энтропии (ΔS2°=90,4 Дж/(моль×К)). Предполагается также, что сложноэфирные карбонильные группы в соединениях 1 и 2 образуют различные водородные связи с рецептором.
|
| issn |
0533-1153 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/42067 |
| citation_txt |
Thermodynamics of 3-hydroxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones esters complexation with the central benzodiazepine receptors / S.P. Smulsky, N.O. Burenkova, S.A. Andronati, V.I. Pavlovsky, P.G. Polishchuk, K.S. Andronati // Журнал органічної та фармацевтичної хімії. — 2012. — Т. 10, вип. 4(40). — С. 65-70. — Бібліогр.: 34 назв. — англ. |
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Журнал органічної та фармацевтичної хімії. – 2012. – Т. 10, вип. 4 (40)
65
УДК 547.892+ 544-971.62+ 615.31
THERMODYNAMICS OF 3-HYDROXY-7-BROMO-5-(2'-CHLORO)
PHENYL-1,2-DIHYDRO-3H-1,4-BENZODIAZEPINE-2-ONES
ESTERS COMPLEXATION WITH THE CENTRAL BENZODIAZEPINE
RECEPTORS
S.P.Smulsky, N.O.Burenkova, S.A.Andronati, V.I.Pavlovsky,
P.G.Polishchuk, K.S.Andronati
A.V.Bogatsky Physico-Chemical Institute of the NAS of Ukraine
65080, Odessa, Lustdorfskaya doroga 86. E-mail: andronati_s@ukr.net
Key words: recognition; radioligand analysis; thermodynamics of complexation; affinity; hydrogen bond;
hydrophobic interactions
The complexation of 3-alkylcarbonyloxy-7-bromo-5-(2'-chloro)phenyl-1,2-dihydro-3Н-1,4-ben-
zodiazepine-2-ones (R=Ме (1), R=t-Bu (2)) with the central benzodiazepine receptors (CBDR) at
six temperatures within the range of 0-35°С has been studied by the radioligand analysis method.
It has been found that formation of the supramolecular complex of compound 1 with CBDR is
endothermic with a rather great and unfavourable change of enthalpy (∆Н1° = +32,3 kJ/mоl),
which is compensated by signifi cant change in entropy (∆S1° = +266,7 J/(mоl×К)). On the
contrary, the binding of compound 2 to CBDR is exothermic (∆Н2° = -20,7 kJ/mоl) and with a
favourable entropy change (∆S2° = +90,4 J/(mоl×К)). The ester carbonyl groups in compounds
1 and 2 are also supposed to form different hydrogen bonds with the receptor.
ТЕРМОДИНАМІКА КОМПЛЕКСОУТВОРЕННЯ ЕСТЕРІВ 3-ГІДРОКСИ-7-БРОМ-5-(2'-ХЛОР)ФЕ-
НІЛ-1,2-ДИГІДРО-3H-1,4-БЕНЗОДІАЗЕПІН-2-ОНІВ З ЦЕНТРАЛЬНИМИ БЕНЗДІАЗЕПІНОВИМИ
РЕЦЕПТОРАМИ
С.П.Смульський, Н.О.Буренкова, С.А.Андронаті, В.І.Павловський, П.Г.Поліщук, К.С.Андронаті
Методом радіолігандного аналізу вивчено комплексоутворення 3-алкілкарбонілокси-
7-бром-5-(2'-хлор)феніл-1,2-дигідро-3Н-1,4-бенздіазепін-2-онів (R=алкіл R=Ме (1), R=t-Bu
(2)) з центральними бенздіазепіновими рецепторами (ЦБДР) при шести температу-
рах у інтервалі 0-35°С. Встановлено, що утворення супрамолекулярного комплексу
сполуки 1 з ЦБДР ендотермічне з доволі великою та несприятливою зміною ентальпії
(∆Н1°=32,3 кДж/моль), яка компенсується значною зміною ентропії (∆S1°=266,7 Дж/(моль×К)).
Зв’язування сполуки 2 з ЦБДР екзотермічне (∆Н2°=-20,7 кДж/моль) зі сприятливою змі-
ною ентропії (∆S2°=90,4 Дж/(моль×К)). Передбачається також, що естерні карбонільні
групи у сполуках 1 і 2 утворюють різні водневі зв’язки з рецептором.
ТЕРМОДИНАМИКА КОМПЛЕКСООБРАЗОВАНИЯ ЭФИРОВ 3-ГИДРОКСИ-7-БРОМ-5-(2'-ХЛОР)
ФЕНИЛ-1,2-ДИГИДРО-3H-1,4-БЕНЗОДИАЗЕПИН-2-ОНОВ С ЦЕНТРАЛЬНЫМИ БЕНЗДИАЗЕ-
ПИНОВЫМИ РЕЦЕПТОРАМИ
С.П.Смульский, Н.А.Буренкова, С.А.Андронати, В.И.Павловский, П.Г.Полищук, К.С.Андронати
Методом радиолигандного анализа изучено комплексообразование 3-алкилкарбонил-
окси-7-бром-5-(2'-хлор)фенил-1,2-дигидро-3Н-1,4-бенздиазепин-2-онов R=Ме (1), R=t-Bu
(2)) с центральными бенздиазепиновыми рецепторами (ЦБДР) при шести температу-
рах в интервале 0-35°С. Обнаружено, что образование супрамолекулярного комплекса
соединения 1 с ЦБДР эндотермическое с довольно большим и неблагоприятным из-
менением энтальпии (∆Н1°=32,3 кДж/моль), которое компенсировано значительным
изменением энтропии (∆S1°=266,7 Дж/(моль×К)). Связывание соединения 2 с ЦБДР
экзотермическое (∆Н2°=-20,7 кДж/моль) и с благоприятным изменением энтропии
(∆S2°=90,4 Дж/(моль×К)). Предполагается также, что сложноэфирные карбонильные
группы в соединениях 1 и 2 образуют различные водородные связи с рецептором.
Analysis of equilibrium formation of supramolecu-
lar complexes of drugs with membrane receptors within
range from 0 to 35°C temperature led to certain genera-
lizations. For the majority of membrane receptors, it
was found ability for thermodynamic discrimination
of ligands as agonists and antagonists. For 184 inde-
pendent experiments and 10 receptor systems the phe-
nomenon of enthalpy-entropy compensation was de-
scribed [1]. The majority of membrane receptors form
supramolecular complexes with drugs and endogenous
Журнал органічної та фармацевтичної хімії. – 2012. – Т. 10, вип. 4 (40)
66
ligands (neurotransmitters) with the temperature in-
dependent enthalpies (∆H) and entropies (∆S) [2].
Information obtained on the basis of thermody-
namic analysis of ligand receptors binding is unique
and is not available if equilibrium constants are mea-
sured at one temperature. Cautious interpretation
of thermodynamic analysis results allows conclud-
ing on the mechanism of complexation and the na-
ture of intermolecular interactions between a ligand
and a receptor in supramolecular complexes, as well
as on the causes of intrinsic activity [2, 3].
Analysis of the binding in dependence of tempe-
rature allows determining free energies and, conse-
quently, the equilibrium constants at different tem-
peratures within a given range (typically from 0 to
35°C), including the constant at body temperature,
what is the closest approximation to the conditions
of pharmacological tests in experimental animals.
The van’t Hoff equation is used in the thermody-
namic analysis
lnKА = -∆Н°/RT + ∆S°/R,
where R – gas constant; T – temperature in Kelvin;
KA – equilibrium association constant of ligand-re-
ceptor complex; ∆Н° and ∆S° are standard enthalpy
and entropy of complexation, respectively. The tem-
perature of 298,15 K (25°C) and atmospheric pres-
sure are the standard conditions as a rule.
GABAA receptor-ionophoric complex belongs to
the superfamily of ionotropic receptors and provides
the Cl¯ and HCO3¯ ion transport into the cell. In ad-
dition to the GABA binding sites, GABAA
ionophoric
complex includes binding sites of benzodiazepines,
picrotoksinin, β-carbolines, barbiturates, and other li-
gands [4]. 1,4-Benzodiazepine derivatives are the most
common and known ligands of the central benzodi-
azepine receptors and are widely used as medicine
neurotropic drugs [4, 5]. Thermodynamic analysis of
binding of drugs of benzodiazepine series (diazepam,
clonazepam, alprazolam and others) with CBDR is
described in [6-13], and results of studies [6-12], are
summarized in the review [3]. The van’t Hoff plots of
the ln(1/Ki) versus the (1/T)×(1000/K) for all ben-
zodiazepines described in the literature are linear
within the temperature range from 0 to 35°C, with
the exception of certain cases, when broken lines of
plots for clonazepam at 21°C [8] and #lunitrazepam
at 10°C were observed [9]. All 1,4 benzodiazepines
described in the literature [6-13], with the exception for
triazolam and dezmethylmedazepam, form exother-
mic complexes with CBDR. It is known from the lit-
erature that changes in the benzodiazepine chemical
structure ambiguously affect the free energy (∆Н°
and ∆S°) of the complexation with CBDR. For example,
molecules of alprazolam and triazolam differ by a chlo-
rine atom in 2 position of 5-phenyl radical, while the
thermodynamic pro#iles of their interaction with CBDR
are diametrically opposed. Alprazolam, containing no
chlorine atom in the 5-phenyl radical, forms an exo-
thermic complex with CBDR, and triazolam, which
contains a chlorine atom in this position, forms an
endothermic complex with the CBDR [10]. At the
same time, #lunitrazenpam, diazepam and nordiaze-
pam not only have close values of free binding ener-
gies at 37°C (∆G°= -48±6, -45±5, -41±4 kJ/mоl), but
also relatively close values of enthalpy (∆Н°=-53±3,
-41±2, -44±7 kJ/mоl) and entropy (Т∆S°=-5±7, +5±5,
-3±8 kJ/mоl) members of free energies [9].
Currently, there are no systematic data of studies
on the relationship between the chemical structure
of the 1,4-benzodiazepines, the degree of activation
of GABAA receptor complex and the structures of free
energies (∆Н°, ∆S°) of their complexation with CBDR.
There are no works on the thermodynamic analysis
of complexation of substituted in the third position
1,4-benzodiazepines with CBDR, despite the fact that
this series of derivatives is very promising concern-
ing the search for new neurotrophic drugs. There are
well known drugs among the representatives of this
series of compounds: lorazepam, oxazepam, temaze-
pam, and others. For a long period of time we carry
out research in molecular design, synthesis and study
of relationship of structure – properties, mode of action
and pharmacology of 1,4-benzodiazepine-2-one de-
rivatives [14-19]. Af#inity and selectivity for central
and peripheral benzodiazepine CNS receptors at the
0°С was examined for many compounds by radioli-
gand analysis [17, 20-26]. However, information ob-
tained at the same temperature is insuf#icient and
doesn’t allow making a decision about driving forces
of complexation and nature of interactions with CBDR
of the investigated 1,4-benzodiazepines. Thereby (and
in continuation of our ongoing research), it was in-
teresting to investigate thermodynamics of comple-
xation of 3-substituted 1,4-benzodiazepin-2-ones (com-
Fig. 1. The van’t Hoff plots showing the affect of temperature on the
association constants (1/Ki) of compounds 1, 2 in the experiment
on the displacement of [3H] fl umazenil. Values 1/Ki are mean of four
independent determinations, each performed in triplicate. Linear
interpolation over the points connected by the continuous line
(0≤t≤35 C) gives correlation coeffi cients, r, in the range of 0.98-0.99.
Журнал органічної та фармацевтичної хімії. – 2012. – Т. 10, вип. 4 (40)
67
pounds 1 and 2, Fig. 1, Scheme 1) with CBDR. The
compounds for which the thermodynamics of bind-
ing to the GABAA receptor complex have been stud-
ied in this paper have highly anxiolytic, anticonvul-
sant and sedative activity and high af�inity for CBDR
[24]. In this paper, compounds 1 and 2 as research
objects were used.
Results and Discussion
The table contains inhibition constants (Ki) for
the compounds 1 and 2 at six temperatures 0, 10,
20, 25, 30 and 35°C, as well as, calculated on the
base of van’t Hoff plots standard enthalpies (∆H°)
and entropies (∆S°) for equilibrium displacement of
[3H]�lumazenil from speci�ic binding sites of CBDR.
The table shows also dissociation constants for [3H]
�lumazenil complex with CBDR, which were used by
us for the calculation of Ki for compounds 1 and 2
by the Cheng-Prusoff equation. The van’t Hoff plots
for compounds 1 and 2, in the studied temperature
range, were strictly linear (Fig. 1).
The binding of compound 1 to the CBDR of the
rats cerebral cortex was accompanied by heat ab-
sorption (∆Н°1 = +32,3 kJ/mоl) and relatively large
increase in entropy (∆S°1 = +266,7 J/(mоl×К)). While
the compound 2 complexation with CBDR was exother-
mic (∆Н°2 = -20,7 kJ/mоl and ∆S°2 = +90,4 J/(mоl×К)),
and was accompanied with temperature increase
which was two-fold lesser. Thus, complexation of
compounds 1 and 2 with CBDR are driven by differ-
ent forces. Thus, the compound 1 complexation with
the receptor is exclusively driven by entropy, while
the compound 2 binding to the receptor is driven by
both enthalpy and entropy.
A well-known generalized model of the receptor
complex with benzodiazepines of Huang Q. et al. [27]
suggests the following features of the molecular in-
teraction of 1,4-benzodiazepine-2-ones with CBDR.
Carbonyl oxygen of the amide group and nitrogen
atom N4 of diazepine ring form hydrogen bonds with
the receptor site. Benzene ring in position 5 and the
ring condensed with 1,4-diazepine cycle, as well as
substituents in position 7, interact with the hydro-
phobic centers of the receptor site. Taking into ac-
count the given model, and keeping in mind the ac-
ceptor properties of the ester carbonyl groups (the
substituents in position 3 of compounds 1 and 2), one
can assume the formation of different hydrogen bonds
with donor regions of CBDR sites (Fig. 2), weak hy-
drogen bond with the receptor for the compound 1,
and stronger one in the case of compound 2. It is
Table
Equilibrium inhibition constants (Ki), dissociation constants (KD) at various temperatures,
standard enthalpies (∆H°) and entropies (∆S°) for complexation
of the compounds 1-4 and [3H]! umazenil with CBDR
Compounds
Ki±SEM [nM] ∆Н°±SEM
(kJ/mol)
∆S°±SEM
(J/(mоl×К))0°С 10°С 20°С 25°С 30°С 35°С
1
16,50
(1,2)
11,80
(1,1)
6,05
(0,4)
6,21
(0,3)
4,56
(0,2)
3,13
(0,1)
+32,3
(3,0)
+266,7
(10)
2
1,91
(0,04)
3,19
(0,15)
3,91
(0,1)
4,19
(0,3)
5,00
(0,2)
5,83
(0,4)
-20,7
(2)
+90,4
(6)
3* +35,1 +305,0
4* +23,4 +191,6
[3H]Flu-mazenil**
KD±SEM [nM]
1,23
(0,05)
2,3
(0,1)
3,2
(0,1)
4,00
(0,2)
4,90
(0,2)
6,30
(0,5)
* Data taken from ref. [10]; ** Data taken from ref. [33]
Fig. 2. Hypothetical scheme of interactions of compounds 1 and 2
with hydrophobic sites and donor sites of hydrogen bonds (indicated
by dotted lines) of CBDR site (based on Huang Q model) [30].Scheme 1
Журнал органічної та фармацевтичної хімії. – 2012. – Т. 10, вип. 4 (40)
68
possible that formation of the hydrogen bonds can
occur either competing for the donor centers of the
receptor with nitrogen atoms N4 or amide carbonyl
groups of the 1,4-benzodiazepine ring or by the for-
mation of new additional hydrogen bonds with do-
nor sites of CBDR. In any case, thermodynamic pro-
�iles of these compounds complexation with the re-
ceptor give indirect evidence in favour of the offered
assumption (Table and Fig. 3). It is generally accept-
ed, that hydrogen bonds formation is accompanied
by decrease of enthalpy and entropy. Therefore, in
whole energetic balance (change in free energy), strong
hydrogen bonds may exceed energy of non-speci�ic
(hydrophobic) interactions, and that often leads to
decrease of the process enthalpy and minor posi-
tive changes in entropy, and in some cases, to its
decrease. Weak hydrogen bonds, which are accom-
panied with insigni�icant decrease of enthalpy, in many
cases, aren’t able to exceed positive change of enthal-
py of non-speci�ic hydrophobic interaction of ligand
with its receptor. As a result, change of complexation
enthalpy may turn out to be a positive one. However,
it is arise of question how to explain the fact that
hydrogen bond in the case of compound 1 (R = Me)
is weaker then hydrogen bond of compound 2 (R =
t-Bu) when they interact with their receptors.
Unfortunately, the involvement of a methyl group
(compound 1) and tert-butyl group (compound 2)
in interaction with CBDR can not be described with-
in the model of Huang Q. et al. [27], because substi-
tuted in the 3 position of 1,4-benzodiazepines are
not taken into account at creation of this model.
According to the results of our long-term research
[28], pharmacological activity of 3-alkyl-substituted
(alkyl = Me, Et, i-Pr and t-Bu) 1,4-benzodiazepines is
inversely related to lipophilicity. Taking into account
these indirect facts and thermodynamic analysis con-
ducted by us on the binding of the compounds 1 and
2 with CBDR, it could be assumed that the t-Bu radical
of the compound 2 does not enter into hydrophobic
interactions with the receptor. The thermodynamic
profiles of the interaction of compounds 1 and 2
with benzodiazepine receptor (∆Н°1 = +32,3 kJ/mоl,
∆S°1 = +266,7 J/(mоl×К), ∆Н°2 = -20,7 kJ/mоl, ∆S°2
= +90,4 J/(mоl×К)) prove this fact. It is seen in the
coordinates -T∆S° versus ∆Н° (Fig. 3) that the driv-
ing forces for the complexation of compound 2 with
CBDR are changes in enthalpy (∆Н°) and entropy (∆S°).
Compound 1, in contrast to compound 2, binds to
the receptor due to the entropy change only.
There are at least two examples in the literature
where the driving force of benzodiazepine comple-
xation with CBDR is the change in entropy. These com-
pounds are triazolam (3) and dezmethylmedazepam
(4), the thermodynamic analysis of the binding of which
was carried out under conditions similar to conditions
of our experiments (on the twice washed membranes
in the presence of 0,2 M NaCl in the incubation me-
dium) [10]. Thus, the compounds 1, 3 and 4 form a
ligand group, which binding with CBDR differs signi-
�icantly from those described in the literature and ben-
zodiazepines studied by us (compound 2) (Scheme 2).
Thermodynamic analysis of complexation of com-
pounds 1, 3 and 4 with CBDR has demonstrated that:
1) compounds 1, 3 and 4 bind to CBDR with the
heat absorption and a large favorable change in en-
tropy (see Table). This means that their interaction
with the receptor is mainly caused by the rearrange-
ment of solvent molecules near the receptor site and
near the interacting ligand molecules. It is generally
accepted that such complexation thermodynamic pro-
�ile mainly is a result of hydrophobic ligand-receptor
interactions [29]:
2) unlike the compound 1, the compound 2 (just
as benzodiazepines described in literature [6-13],
with the exception of the compounds 3 and 4) forms
exotermic complex with CBDR.
It is known not only numerous multi-center re-
lationships and interactions, but also the reorgani-
zation of a solvent contribute to the free energy of
ligand-protein (receptor) complexation. It is consid-
ered that the only theoretical calculation is able to dif-
ferentiate these contributions and to correlate them
with structural fragments of molecules of ligands and
receptors [30, 31].Our results on the thermodynam-
ics of binding of the esters (compounds 1 and 2) to
CBDR, as well as literature data, for example [10], on
Fig. 3. Represent the thermodynamic data of the interaction of
compound 1 (●) and 2 (▲) with CBDR in the coordinated -TDS°
versus ∆Н° (were KA=104 M-1 and KA=1011 M-1 are lower and upper
limits of values of association constants of the drugs, respectively,
with bioreceptors, see ref. 1).
Scheme 2
Журнал органічної та фармацевтичної хімії. – 2012. – Т. 10, вип. 4 (40)
69
the binding of alprazolam, triazolam and dezmethyl-
medazepam to benzodiazepine receptors demonstra-
te that the thermodynamics of the formation of supramo-
lecular ligand-CBDR complexes can be extremely sen-
sitive to changes in the ligand chemical structure.
Changes of standard entropies of complexation
of compounds 1, 3, 4 allow supposing that the rear-
rangement of solvent molecules is the main reason
for the change of the free energies of complexation
of these compounds with CBDR and it demonstrates
that the thermodynamics of the formation of supra-
molecular ligand-CBDR complexes can be extremely
sensitive to changes in the ligand chemical structure.
There is no yet satisfactory explanation of the fact
concerning the dominant participation of nonspeci-
!ic interactions of the studied compound 1 as com-
pared to compound 2, at the formation of complex
with benzodiazepine receptors. These differences are
dif!icult to explain without pharmacophore-recep-
tor models for 3-substituted 1,4-benzodiazepines. We
hope that further investigation of thermodynamics
of complexation in the series of 3-substituted 1,4-ben-
zodiazepines with CBDR will contribute to the clari-
!ication of this interesting fact and may be used in
the further development of models of the complex
1,4-benzodiazepin – CBDR.
Experimental part
Compounds 1-2 were synthesized using litera-
ture procedures [32].
In vitro receptor binding assays. [3H]Flumaze-
nil binding
Adult male Wistar rats with a body weight of 180-
220 g were maintained under an arti!icial 12-h-light/dark
cycle (light on 08.00 to 20.00 h). Food and water were
freely available until the time of the experiment. An-
imal care and handling throughout the experimental
procedures were in accordance with the European
Communities Council Directive of 24 November 1986
(86/609/EEC). The experimental protocols were ap-
proved by the Animal Ethical Committee of the Uni-
versity of Cagliari. Af!inity of compounds 1, 2 for CBDR
of rat brain was determined by modified method
and values of ІС50 were evaluated.
Animals were anesthetized and decapitated, the
cerebral cortex was quickly extracted and homoge-
nized in 30 ml of 0,05 M ice-cold citrate buffer (pH 7,1
at 4°С) with a Dounce homogenizer. The homogen-
ate was centrifuged at 20 000 g for 15 min at 4°С.
The pellet was resuspended in initial volume of the
same buffer and centrifuged again under the same
conditions. The process of homogenization and cen-
trifugation was repeated for 2 times. Supernatant was
decanted, the residue was resuspended in 0,05 M of
ice-cold incubation citrate buffer containing 200 mM
NaCl to obtain the suspension with wet membrane con-
centration of 50 mg/ml and adjusted for each tem-
perature.
Thermodynamic analysis of the formation of com-
plexes of compounds 1, 2 with CBDR was carried out at
temperatures of 0, 10, 20, 25, 30 and 35°C. Determi-
nation of equilibrium binding constants (KA = 1/Ki)
for the binding of compounds 1, 2 to membrane com-
plex of the rats cerebral cortex was carried out in
0,5 cm3 of tris-citrate incubation buffer pH 7,1, ad-
justed for each temperature. The incubation time
ranged from 75 min at 0°C to 20 min at 35°C [33].
Nonspeci!ic binding (which was no more than 10%)
of the radioligand [3H] !lumazenil ([3H]Ro15-1788)
was determined in the presence of 1×10-6mol/dm3
cold flumazenil. To determine the semi-inhibitory
concentrations (IC50) for the compounds 1, 2 eight
concentrations were used for each compound, rang-
ing from 0,1×10-9 to 1×10-6×mol/dm3. Inhibition con-
stant Ki was calculated using the Cheng-Prusoff for-
mula (Ki = IC50/(1+[L]/KD)) [34], where IC50 – con-
centration of test ligand at which is observed 50%
radioligand displacement from speci!ic binding sites
of the receptor, [L] – total concentration of radioli-
gand, KD – dissociation constant of the radioligand
complex with the CBDR for each of the experimental
temperatures, taken from [33]. The standard free ener-
gies (∆G°) of compounds 1, 2 complexation were calcu-
lated by the equation of van’t Hoff (∆G° = -RTln(1/Ki)).
The standard enthalpy (∆Н°) and entropy (∆S°) of
complexation were obtained by regression analysis
from the slope of the van’t Hoff plots (-∆Н°/RT) and
the intersection plots (-∆S°/R) with the ordinate axis,
where T = 298,15 K, R = 8,314 J/(mol×K).
Conclusion
1. Enthalpy and entropy of the compounds 1 and
2 complaxetion are more sensitive to changes in their
chemical structure, than free energy.
2. Driving forces of complexation of the compounds
1 and 2 with CBDR are different. The compound 1
binds to receptor solely due to the changes in both
enthalpy and entropy.
3. It is suggested that the compounds 1 and 2 form
different in respect to energy hydrogen bonds with
the receptor.
Acknowledgments
This work was supported by funds for funda-
mental investigations of NAS of Ukraine and CNRS
(PICS 2010-2012).
Журнал органічної та фармацевтичної хімії. – 2012. – Т. 10, вип. 4 (40)
70
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