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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.

Asymmetric hydrosilylation of acetophenoxime and cyclic and acyclic imines (with subsequent hydrolysis to amines) was investigated using as catalyst a rhodium complex with the chiral phosphinamino ligand (S)-Phephos. With this method the chiral analog of the antidepressant Pyrazidol was synthesized with an optical yield of 73%.

New arbidol analogs of the indole and benzofuran series were synthesized. The phenyl in them was replaced with substituted phenyl or separated from the sulfide bridge by a methylene group. The antivirus activity of the synthesized compounds was studied using enzyme-linked immunoassay and a murine influenza-induced pneumonia model. Both 5-hydroxyindole and 5-hydroxybenzofuran derivatives were found to have antiviral activity.

A method of synthesizing 2-acetylamino-7-hydroxy-6-phenylthio-3-carbethoxybenzo[b]thiophenes from 6-phenylthio-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophenes has been developed. A method is also proposed for synthesis of 7-phenylthiobenzothieno[2,3-d]pyrimidines.

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.

Results of search for new beta-adrenoreceptor blocking agents of different effects are summarized. Derivatives of 4-hydroxyindolyl-3-acetic acid are characterized by a prolonged beta-adrenoblocking effect, cardioselective beta-adrenoblockers were found among derivatives of N,N-bis(2-hydroxy-3-phenoxypropanol)amine, and highly effective "hybrid" beta-,a-adrenoblockers were detected among derivatives of 3(5)-phenoxymethylisoxazolines and 5-phenoxymethyl-1,2,4,-oxadiasoles. Clinical studies of one of the most promising compounds of the latter series named proxodolol showed it to be a highly effective antihypertensive, antianginal, and antiglaucoma drug. Proxodolol is permitted for clinical application. At present it is manufactured as eye drops for decreasing intraocular pressure in glaucoma; its production as a solution for injections for arresting hypertensive crises is starting.

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.

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 μM) than that of GABAA receptors. Pirlindole was inactive as a GABA antagonist. Dehydro-pirlindole exhibited selective blockade of GAB A-A receptors with EC50 12 μM. 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.

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.

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.

The antidepressive effects of tetrindole versus pyrazidole (pirlindole) and imipramine were studied in animal experiments. Tetrindole was found to be more active than pyrazidole and imipramine in a behavioral model of Porsolt, in antagonism with reserpine, in potentiation with 5-hydroxytryptophan, L-dopa and clonidine. The action of terindole is related to its ability to exert reversible inhibitory effects on MAO A activity. Tetrindole is less toxic than pyrazidole and imipramine.

1. 3-(1-Adamantyl)-3-chloropropenal is a useful synthon for obtaining adamantyl-substituted nitrogen heterocycles: 2-(1-adamantyl)quinoline, 2-(1-adamantyl)-6-bromoquinoline, 6-(1-adamantyl)pyrimidine, 1-phenyl-5-(1-adamantyl)pyrazole, and 6-(1-adamantyl)thieno[2,3-e]pyrimidin-4-one. 2. X-ray crystallographic analysis points to the trans configuration of the aldehydic and adamantyl substituents on the C=C double bond in the molecule of 3-(1-adamantyl)-3-chloropropenal which is characterized by near Cs symmetry. A small increase in the C-Cl bond length in this molecule is probably due to a weak intermolecular attractive interaction at a distance of 3.447(2) A.