2-H- and 2-acyl-9- [omega-[4-(2-methoxyphenyl)piperazinyl]-alkyl]-1,2,3,4-tetrahydro-beta-carbolines as ligands of 5-HT1A and 5-HT2A receptors.

Three series of new unsubstituted or 2-acyl 1,2,3,4-tetrahydro-beta-carbolines (THBC), connected to 1-(o-methoxyphenyl)piperazine by 2-, 3- or 4-membered alkylene spacer (3, 4 or 5, respectively) in position 9, were synthesized and their 5-HT1A/5-HT2A receptor affinities and functional in vivo activities were investigated. Radioligand binding studies showed that unsubstituted (a) and acyl (b-f) derivatives with prop-1,3-ylene (4) and particularly with but-1,4-ylene (5) spacer had a high 5-HT1A receptor affinity (Ki = 30-110 nM), whereas the 5-HT1A affinity of derivatives with ethylene spacer (3) was low. All those compounds (except 5c, Ki = 44 nM) did not distinctly bind to 5-HT2A receptors. The obtained results indicated that the length of an alkylene chain was a crucial parameter for determining 5-HT1A receptor affinities of the tested compounds, while acyl substituents in position 2 of THBC were not important for their 5-HTIA/5-HT2A activities. It was also demonstrated that the few selected compounds (4d, 5a-c and 5e) with the highest affinity (Ki up to 50 nM) for 5-HT1A receptors, administered at doses of 10-20 mg/kg, behaved like antagonists of postsynaptic 5-HT1A receptors, as they reduced the 8-OH-DPAT (5-HT1A agonist)-induced lower lip retraction and behavioral syndrome in rats. Moreover, 4d seemed to be an agonist of presynaptic 5-HT1A receptors, since the hypothermia induced by its administration was attenuated by WAY 100635 (5-HT1A antagonist). Compound 5c, 5-HT2A receptor ligand, demonstrated an antagonistic activity, as it inhibited the (+/-)DOI (5-HT2A agonist)-induced head twitches in mice. The obtained results of in vivo studies suggest that introduction of different acyl substituents in position 2 of THBC with propylene or butylene spacer between tricyclous and arylpiperazine moiety is insignificant for the postsynaptic 5-HTIA receptor activity of the compounds tested in vivo. On the other hand, only compound 5c with an acryloyl group and a butylene chain behaved like a 5-HT1A/5-HT2A antagonist.

A search for new 5-HT1A/5-HT2A receptor ligands. In vitro and in vivo studies of 1-[omega-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-ones.

A series of 1-¿omega-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-one derivatives 2-14 was synthesized in order to obtain ligands with a dual 5-HT1A/5-HT2A activity. The majority of those compounds (2-5, 7, 10-13) exhibited a high 5-HT1A (Ki = 2-44 nM) and/or 5-HT2A affinity (Ki = 51 and 39 for 5 and 7, respectively). Induction of lower lip retraction (LLR) and behavioral syndrome and inhibition of these effects evoked by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were used for determination the agonistic and antagonistic activity, respectively, at 5-HT1A receptors. The 5-HT2A antagonistic activity was assessed by the blocking effect on the head twitches induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice. Two of the tested compounds, 1-¿3-[4-(3-chlorophenyl)-1-piperazinyl]propyl¿-6-fluoroindolin-2(1 H)-one (5) and 1-¿3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl¿indolin-2(1H)-one (7), demonstrated a high 5-HT1A/5-HT2A affinity and an in vivo antagonistic activity towards both receptor subtypes.

5-HT1A and 5-HT2A receptor affinity and functional profile of some N-[3-(4-aryl-1-piperazinyl)propyl] derivatives of indolin-2(1H)-one, quinolin-2(1 H)-one and isoquinolin-1(2H)-one. Part 30: Structure-activity relationship studies of CNS agents.

A series of new 1-aryl-4-propylpiperazines containing the modified terminal amide fragment 9, 15-19, 21, 23 and 25 were synthesized and their 5-HT1A and 5-HT2A receptor affinities were determined. All the compound were highly potent 5-HT1A receptor ligands with a diverse 5-HT2A receptor affinity. It was found that the 5-HT2A receptor affinity depends on the dipole moment and lipophilicity of amide moiety. Compound 9b was found to be a 5-HT2A receptor antagonist and a weak 5-HT1A receptor agonist.

4-Aryl-1-piperazinylalkyl derivatives of 1,2,3,4-tetrahydro-beta-carboline ring system. Synthesis and preliminary in vivo studies.

Three series of compounds containing a 4-aryl-1-piperazinylalkyl fragment attached to a different position of the indole (A) or 1,2,3,4-tetrahydro-beta-carboline (B, C) have been prepared. The quantitative relationship between the structure of some derivatives and their sedative effect was found using the Free-Wilson approach.

[Local use of cyclosporin in nonbacterial corneal ulceration]. / Miejscowe zastosowanie cyklosporyny w niebakteryjnych owrzodzeniach rogówki.

The authors present the results of local use of cyclosporin solution in 6 patients with corneal ulcerations occurring in Sjögren disease, rheumatic disease and after corneal transplantation. The ulceration was healed in all patients. The cyclosporin, locally applied, has no side effects and may be an efficient way in the treatment of some immunological diseases of cornea.

Structure-activity relationship studies of CNS agents. Part 9: 5-HT1A and 5-HT2 receptor affinity of some 2- and 3-substituted 1,2,3,4-tetrahydro-beta-carbolines.

The 5-HT1A and 5-HT2 receptor affinity of 2- and 3-substituted 1,2,3,4-tetrahydro-beta-carbolines 1-8, 10 and 12-15 has been determined. It has been found that the specific 5-HT1A affinity of the protonated form (KiAH+) 2-n-hexyl derivatives 4, 8, 14 and (+)-LSD is of the same order. It has been shown by means of molecular modelling methods that pharmacophores of all the active compounds can adopt a common position at the 5-HT1A receptor model. The model also offers an explanation for the observed stereoselectivity chiral compounds.

Structure-activity relationship studies of CNS agents. Part 4: 2-[3-(4-aryl-1-piperazinyl)propyl]-1,2,3,4-tetrahydro-beta-carbolin+ ++ -1-one derivatives as potential central anti-serotonin agents.

Seven derivatives of 1,2,3,4-tetrahydro-beta-carbolin-1-one have been prepared. Three of them showed significant central anti-serotonin activity, comparable with that of trazodone or etoperidone. Some structural features were found to be important for the central antiserotonin activity of the investigated class of compounds.

[Examination of the visual system in boxers]. / Badania ukladu wzrokowego zawodników klubów bokserskich.

Ophthalmological examinations were performed in 139 boxers. They showed that the injuries concerned most frequently the ocular adnexa and not the eye globe itself. Only two contestants who practiced boxing for more than 10 years exhibited peripheral opacities of the lens and pale foci with shifting of the pigment at the fundus periphery connected with a deepening of the filtration angle; this could be caused by a contusion of the eye. It was demonstrated that the introduction of safety helmets distinctly reduced the number of eye injuries in boxing.

Structure-activity relationship studies of CNS agents. Part 1: The Free-Wilson analysis of acute toxicity and sedative effect of some 1,2,3,4-tetrahydro-beta-carbolines.

It has been found that 3-alkoxycarbonyl-beta-carbolines are almost non-toxic and showed a sedative effect. The quantitative relationship between the structure of some 1,2,3,4-tetrahydro-beta-carbolines and their acute toxicity and sedative effect was found using the Free-Wilson approach.

N-aminoalkylderivatives of 1,2,3,4-tetrahydro-beta-carboline-1-spiro-4'-N'- benzylpiperidine--a putative way to novel anxiolytic agents.

A series of aminoalkylderivatives of 1,2,3,4-tetrahydro-beta-carboline-1-spiro-4'-N'-benzylpiperidine were synthesized by means of chloroacetylation of the title compound and substitution of chlorine atom with various heterocyclic amines in DMSO, followed by LAH reduction of the carbonyl group. Of the ten tested compounds (4a-4e, 5a-5e), compound 5d given ip, but not orally, showed an anxiolytic activity in the four-plate test in mice and in the conflict test in rats. Compound 5d is devoid of an anticonvulsant or neurotoxic action. The activity of compound 5d resembles this of buspirone.

Synthesis and pharmacological properties of decahydro-5H-pyrido [1',2';5,1] imidazo [3,4-a]-beta-carbolines. Part II.

Ten cyclic animals (1-10), including a form of decahydro-5H-pyrido [1',2';5,1] imidazo [3,4-a]-beta-carboline, were obtained by treating erythro 1-(2'-piperidyl)-1,2,3,4-tetrahydro-beta-carboline with aldehydes. The anticonvulsant action of those compounds (1-10) was investigated in mice using a behavioral test. Only 5-(3-chlorophenyl) (2) and 5-(3-pyridyl) (9) derivatives showed an anticonvulsant activity in the electric seizure test, but their therapeutic index was inferior to that of phenytoin.

Synthesis and pharmacological properties of some 2-(3-aminopropionyl)- and 2-(3-aminopropyl)-1-(3-pyridyl)-1,2,3,4-tetrahydro-beta-carbolines.

Five derivatives of 2-(3-aminopropionyl)-1-(3-pyridyl)-1,2,3,4-tetrahydro-beta-carboline (2a-e) were obtained, which yielded, as a result of reduction with LiAlH4, five respective 2-aminopropyl-derivatives (3a-e). Pharmacological studies revealed that phenylpiperazine-derivatives 2d, 2e, 3d and 3e have sedative and analgesic properties. All compounds are devoided of neuroleptic, antidepressant, anxiolytic and antiparkinsonic activity.

Synthesis of N-nicotinoyl-tryptamine (tryptamide).

N-Nicotinoyl-tryptamine was synthetized by acylation of tryptamine with mixed nicotinic anhydride. The synthesis of tryptamine via DL-tryptophan decarboxylation in cyclohexanol, in the presence of tetraline oxidation products as the catalyst, was described as well.

Synthesis and pharmacological properties of some 2-substituted 1-(3-pyridyl)-1,2,3,4-tetrahydro-beta-carbolines.

Six derivatives of 2-aminoacetyl-1,2,3,4-tetrahydro-beta-carboline (2a-f) were obtained, which yielded as a result of reduction with LiAlH4 six respective 2-aminoethyl-derivatives (3a-f). Pharmacological studies revealed that compounds 2f, 3e and 3f have sedative properties. None of the compounds possesses neuroleptic, antidepressive, anxiolytic, analgesic or anticonvulsant properties.

1-Pyridyl-3,4-dihydro-beta-carbolines: synthesis and central action.

1-Pyridyl-3,4-dihydro-beta-carbolines (2a-2f) were synthesized by two methods. The central action of these compounds was investigated in mice and rats using behavioral tests. The most active 6-methoxy-1-(3-pyridyl)-3,4-dihydro-beta-carboline (2e) possesses potential antidepressant properties, as it reversed the effects of reserpine (sedation, hypothermia and ptosis), potentiated the stimulation induced by levodopa given jointly with pargyline, and reduced the immobility time in the despair test. Moreover, compound 2e inhibited the spontaneous locomotor activity, evoked tremor and produced an analgesic effect.

Synthesis and pharmacological properties of decahydro-5H-pyrido [1',2'; 5,1]imidazo[3,4-a]-beta-carbolines.

Cyclic aminals (1-4) including a form of decahydro-5H-pyrido[1', 2'; 5, 1] imidazo [3, 4-a]-beta-carboline were obtained by treating erythro 1-(2'-piperidyl)-1,2,3,4-tetrahydro-beta-carboline with aldehydes. The central action of compounds 1-4 has been investigated using behavioral tests in mice and rats. The most active aminal was a phenyl derivative 4, which showed an anticonvulsive activity in the maximal electroshock seizure test. The overall activity of compound 4 was less potent than that of phenytoin.

Synthesis and pharmacological properties of N-arylpiperazine-N'-alkylindanes.

Ten new compounds, N-aryl substituted piperazinealkylindanes, have been synthesized. The most active one 1-(2-[4-(3-chlorophenyl)-1-piperazinyl]-ethyl)-indane (compound 9), displayed evident central serotoninolytic properties in the 5-hydroxytryptamine (5-HTP) head twitch test in mice, as well as in the tryptamine convulsions test and the quipazine-stimulated hind paw flexor reflex test in rats.