ABSTRACT
A correlation between the character of pharmacological activity and the energies of electronic transitions in some biologically active molecules, affecting the nervous system, has been found. In order to explain the correlation, a new principle of the membrane ion selectivity filter has been suggested. The principle is based on the recombination process of a metal cation, passing through the filter, with an electron, when the energy quantum (equal to the metal ionization energy) is emitted. The amino acid residue group, performing the function of the channel filter, absorbs this quantum, transits itself into an electronically excited state, changes its conformation and lets, as a result, the cation pass. The process is possible only in that case when the amino acid residue group has a transition of the same energy, therefore not all of metals can pass through the filter. From the viewpoint of this conception, an active molecule acts because of its transition into an electronically excited state of the same energy and interfering, thereby, with the natural processes.
Subject(s)
Cell Membrane Permeability , Cell Membrane , Ion Channels , Animals , Electron Transport , Humans , Ion TransportABSTRACT
A series of pirlindole analogues were tested as inhibitors of monoamine oxidase A and B. Although we did not find strict dependence between 3D-size of molecules and their inhibitory potency, rigid analogues exhibited potent and selective inhibition of MAO-A. They have 3D size limits of 13 angstroms (length) x 7 angstroms (height) x 4.4 angstroms (widths). Besides MAO-A inhibition flexible analogues also demonstrated potent inhibition of MAO-B. Five compounds were studied as inhibitors of purified human liver MAO-A. Their inhibitory potencies coincided with those obtained using rat liver mitochondrial MAO-A. Each compound induced changes in the spectrum of MAO-A but these did not correlate with the flexibility of the derivative. It is also possible that the oxygen bridge introduced with the flexibility might influence spectral patterns.
Subject(s)
Carbazoles/pharmacology , Computer Simulation , Models, Molecular , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/drug effects , Animals , Carbazoles/chemistry , Humans , Mitochondria, Liver/drug effects , Mitochondria, Liver/enzymology , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemistry , Placenta/drug effects , Placenta/enzymology , RatsABSTRACT
A series of pyrazinocarbazoles, analogues of short acting antidepressant pirlindole (2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]carbazole hydrochloride), were tested as inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B). Rigid analogues exhibited potent and selective inhibition of MAO-A and have size limits (X:Y:Z) of 13.0 x 7.0 x 4.4 A. Besides MAO-A inhibition flexible analogues also demonstrated potent inhibition of MAO-B and in contrast to rigid analogues their inhibitory activity did not show the dependence on these sizes. The qualitative information (steric and electrostatic coefficients) from the 3D-QSAR with CoMFA models for MAO-A and -B are different, and this information can be used to determine the structural features influencing inhibitor selectivity.
Subject(s)
Carbazoles/chemistry , Carbazoles/pharmacology , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/chemistry , Animals , In Vitro Techniques , Isoenzymes/chemistry , Isoenzymes/metabolism , Mitochondria, Liver/drug effects , Mitochondria, Liver/enzymology , Models, Molecular , Monoamine Oxidase/metabolism , Protein Conformation , Rats , Structure-Activity RelationshipABSTRACT
The influence of pirlindole and dehydro-pirlindole on GABAA receptor binding and MAO-A activity was investigated in vitro. Inhibition of rat brain and human placenta MAO-A by both compounds was much more potent (with IC50 range 0.3-0.005 microM) than that of GABAA receptors. Pirlindole was inactive as a GABA antagonist. Dehydro-pirlindole exhibited selective blockade of GABA-A receptors with EC50 12 microM. Effects of both compounds on MAO-A activity were partially reversible. Data obtained suggest that in contrast to pirlindole dehydro-pirlindole may act not only as a MAO-A inhibitor but also as a potent GABAA receptor blocker.
Subject(s)
Antidepressive Agents/pharmacology , Carbazoles/pharmacology , GABA Antagonists/pharmacology , Isoenzymes/antagonists & inhibitors , Mitochondria/enzymology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Receptors, GABA-A/metabolism , Animals , Benzodiazepinones/pharmacology , Brain/enzymology , Carbolines/pharmacology , Clozapine/pharmacology , Female , Humans , Kinetics , Mitochondria, Liver/enzymology , Placenta/enzymology , Pregnancy , Rats , Receptors, GABA-A/drug effectsABSTRACT
The effects of pirlindole and dehydro-pirlindole on GABAA receptors and MAO-A activity were investigated in vitro. Pirlindole was inactive as a GABA antagonist. Dehydro-pirlindole exhibited partial and selective blockade of a subset of GABAA receptors with an EC50 of 12 microM and maximum reversal (delta Bopt) of 42%. Inhibition of rat brain and human placenta MAO-A by both compounds was much more potent (with IC50 range 0.3-0.005 microM). Their effects on MAO-A activity were partially reversible in vitro. In contrast to pirlindole, dehydro-pirlindole may act not only as MAO-A inhibitor but also as a clozapine-like selective GABAA receptor blocker, preferentially blocking a subset of GABAA receptors that are not sensitive to DMCM or Ro 5-4864.
Subject(s)
Carbazoles/pharmacology , GABA Antagonists/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Receptors, GABA/metabolism , Animals , Antidepressive Agents/pharmacology , Brain/enzymology , Female , Humans , Placenta/enzymology , RatsABSTRACT
The effects of the antidepressant pyrazidol (pirlindole) and its nitro analog on cGMP-dependent phosphodiesterase from the soluble fraction of human brain cortex have been studied. Pirlindole inhibits the cGMP-induced activity of phosphodiesterase (IC50 = 1585 microM) without influencing the basal activity; its action is noncompetitive in respect of the substrate and the activator. Nitropirlindole is a more potent inhibitor of cGMP-dependent phosphodiesterase (IC50 = 115 microM) competing with the substrate for the catalytic site (K(i) = 70 microM). There is no direct interaction of pirlindole (pyrazidol) and its nitro analog with the cGMP-specific site in phosphodiesterase.
