ABSTRACT
A series of new 1,3-dimethyl-7-phenylalkyl-8-[3-(4-phenyl-1-piperazinyl)propylamino]-purine-2,6-dione derivatives (10-16) was synthesized and their 5-HTIA and 5-HT2A receptor affinities were determined. It was found that compounds with the phenylpropyl substituent in position 7 of purine-2,6-dione (12, 14 and 16), or with phenylmethyl in position 7 and 2-OCH3 in the phenylpiperazine part (13) showed a distinct affinity for 5-HTIA receptors (Ki = 8-50 nM). No structural modifications resulted in 5-HT2A ligands, since the affinity of 10-16 for those receptors was insignificant (Ki = 115-550 nM). The new 5-HT1A receptor ligands (12-14, 16) were investigated in vivo to determine their functional activity at those receptors. In behavioral studies, 12-14 and 16 behaved like postsynaptic 5-HTIA receptor antagonists, since they reduced lower lip retraction and the behavioral syndrome induced by 8-OH-DPAT (5-HT1A receptor agonist) in rats. When given alone, none of the compounds investigated in vivo, mimicked 8-OH-DPAT activity in those tests. Derivative 12 did not affect the body temperature in mice, whereas 13, 14 and 16 decreased it. Furthermore, 12 did not change the hypothermia induced by 8-OH-DPAT, and the decrease in body temperature in mice induced by 13, 14 or 16 was not antagonized by WAY 100635 (5-HT1A receptor antagonist); hence in that model neither 12, 13, 14 nor 16 acted as antagonists or agonists, respectively, at presynaptic 5-HT1A receptors.
Subject(s)
Piperazines/chemistry , Purines/chemistry , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemistry , Animals , Behavior, Animal/drug effects , Binding, Competitive , Body Temperature/drug effects , Cerebral Cortex/metabolism , Hippocampus/metabolism , Ligands , Lip/drug effects , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Mice , Piperazines/chemical synthesis , Piperazines/pharmacology , Purines/chemical synthesis , Purines/pharmacology , Radioligand Assay , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1 , Reserpine/pharmacology , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
Two series of 1-phenylpiperazinylpropyl derivatives 10, 11, 16, 17 and 19-24, structurally related to previously described 5-HT1A or 5-HT2A ligands 4 and 1, respectively, were synthesized and their binding properties were determined. Structural modifications which involved 1,3-diazepine ring opening in 4 (compounds 10, 11, 15, 16) and replacement of spiroalkyl moiety in 1 by aryl substituent (19-24) did not improve binding affinity and selectivity of the tested compounds. The results showed, however, that the diazepine ring present in 4 or spiroalkyl ring in 1 are important for high 5-HT1A or 5-HT2A binding affinity and selectivity of these compounds.
Subject(s)
Purines/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Agents/chemical synthesis , Animals , Chromatography, Thin Layer , In Vitro Techniques , Indicators and Reagents , Ligands , Magnetic Resonance Spectroscopy , Mass Spectrometry , Purines/pharmacology , Pyrrolidines/pharmacology , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin, 5-HT1 , Serotonin Agents/pharmacology , Spectrophotometry, UltravioletABSTRACT
Several derivatives of diphenylimidazolidine-2,4-dione and diphenylimidazolidin-4-one acetic and propionic acids have been synthesized. Some of them were screened for their effect on the CNS in mice and rats. All the investigated compounds showed an analgesic activity. The most active one was 1-benzyl-5,5-diphenyl-3-imidazolidine-2,4-dione acetic acid. That compound exerted an inhibitory activity against the CNS, anxiety-relieving, anticonvulsant and antidepressive effects.
Subject(s)
Acetates/chemical synthesis , Analgesics/chemical synthesis , Imidazoles/chemical synthesis , Propionates/chemical synthesis , Acetates/pharmacology , Acetates/toxicity , Animals , Anti-Anxiety Agents , Anticonvulsants , Catalepsy/chemically induced , Catalepsy/prevention & control , Chemical Phenomena , Chemistry , Chromatography, Thin Layer , Female , Imidazoles/pharmacology , Imidazoles/toxicity , Male , Mass Spectrometry , Mice , Motor Activity/drug effects , Propionates/pharmacology , Propionates/toxicity , Psychomotor Performance/drug effects , Rats , Rats, Inbred Strains , Restraint, Physical , Stereotyped Behavior/drug effectsABSTRACT
In the search for pharmacologically active derivatives of xanthone there were obtained amino alcohol derivatives of 2 methylxanthone (I-V). Effects of compounds Ia, IIa, III and IVa on the circulatory system were investigated.
Subject(s)
Amino Alcohols/therapeutic use , Arrhythmias, Cardiac/drug therapy , Xanthenes/therapeutic use , Xanthones , Amino Alcohols/chemical synthesis , Animals , Anti-Arrhythmia Agents , Arrhythmias, Cardiac/physiopathology , Chemical Phenomena , Chemistry , Hemodynamics/drug effects , Hemodynamics/physiology , Male , Rats , Rats, Inbred Strains , Xanthenes/chemical synthesisABSTRACT
Novel 7,8-disubstituted theophyllines 1-6a, with chiral or achiral moiety of 1,2-aminoalcohol in position 8, were obtained as the compounds with expected activity on circulation. Preliminary evaluation of their antiarrhythmic activity and the effect on the cardiovascular system was carried out. The antiarrhythmic activity similar to that of quinidine (with ca. 20 times lower toxicity) was found only for racemic 7-beta-hydroxyethyl-8-(1'-hydroxybut-2'-yl) aminotheophylline 1 and its enantiomers 2, 3 which did not differ markedly in their efficacy. The compounds with the hydroxyethyl moiety in position 7 of theophylline (1-3, 5) showed the hypotensive effect.
