ABSTRACT
Following a research program on piperazinoalkyl-substituted tricyclic purines, a number of N-9-aryl(alkyl)-piperazinopropyl substituted tetrahydropyrimido-[2,1-f]-purines were synthesized and tested pharmacologically with respect to their influence on the central nervous system. Two of the new compounds induced hypothermia and decreased the spontaneous locomotor activity of mice.
Subject(s)
Central Nervous System Agents/chemical synthesis , Purines/chemical synthesis , Pyrimidines/chemical synthesis , Amphetamine/antagonists & inhibitors , Amphetamine/pharmacology , Animals , Anti-Anxiety Agents/pharmacology , Anticonvulsants/pharmacology , Antipsychotic Agents/pharmacology , Body Temperature/drug effects , Catalepsy/chemically induced , Catalepsy/prevention & control , Central Nervous System Agents/pharmacology , Central Nervous System Agents/toxicity , Lethal Dose 50 , Magnetic Resonance Spectroscopy , Male , Mice , Motor Activity/drug effects , Pentylenetetrazole , Purines/pharmacology , Purines/toxicity , Pyrimidines/pharmacology , Pyrimidines/toxicity , Rats , Rats, Wistar , Seizures/chemically induced , Seizures/prevention & controlABSTRACT
A series of tricyclic, highly water-soluble theophylline derivatives (pyrimido[2,1-f]-theophyllines) containing a basic side chain was investigated in rat brain A1- and A2 adenosine receptor binding assays, phosphodiesterase assays, and benzodiazepine binding studies. Among the new compounds adenosine receptor antagonists with affinities in the same range as the parent compound theophylline were identified. In addition, some compounds were selective for the A1 adenosine receptor subtype. The compounds generally exhibited lower inhibitory activity at brain phosphodiesterases than the parent theophylline. Two compounds were found to show an about 10-fold affinity for benzodiazepine binding sites compared with caffeine and theophylline.
Subject(s)
GABA-A Receptor Antagonists , Phosphodiesterase Inhibitors/chemical synthesis , Receptors, Purinergic P1/drug effects , Theophylline/analogs & derivatives , Theophylline/pharmacology , Animals , Binding, Competitive/drug effects , Caffeine/pharmacology , Guanosine Triphosphate/metabolism , In Vitro Techniques , Membranes/drug effects , Membranes/metabolism , Phenylisopropyladenosine/pharmacokinetics , Phosphodiesterase Inhibitors/pharmacology , Rats , Rats, Wistar , Solubility , Structure-Activity Relationship , Theophylline/chemistryABSTRACT
Synthesis and the results of preliminary pharmacological evaluation of four new 9-substituted pyrimidino[2,1-f]purines, containing pyrimidinyl-piperazine substituent are described. Some of these substances induced hypothermia, antagonism of amphetamine action and neurotoxic effects. All compounds had weaker activity on the central nervous system than previously studied compounds containing phenyl-piperazine substituent.
Subject(s)
Brain/drug effects , Psychotropic Drugs/pharmacology , Purines/pharmacology , Animals , Male , Mice , Psychotropic Drugs/adverse effects , Psychotropic Drugs/chemistry , Purines/adverse effects , Purines/chemistry , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Two series of N10 substituted derivatives of 1,3-dimethyl-2,4,9-trioxo-1,3,6,7,8,10-hexahydro-1,3-diazepino+ ++-[2,1-f]- purine and 1,3-dimethyl-2,4-dioxo-1,3,6,7,8,9-hexahydro-10H-1,3-dizepino- [2,1-f]-purine were synthesized and tested for CNS activity. The most active in central nervous system tests were compounds [II] and [XIV].
Subject(s)
Behavior, Animal/drug effects , Central Nervous System Agents/chemical synthesis , Purines/metabolism , Theophylline/analogs & derivatives , Animals , Central Nervous System Agents/pharmacology , Central Nervous System Agents/toxicity , Drug Design , Drug Interactions , Lethal Dose 50 , Male , Mice , Purines/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Theophylline/chemistry , Theophylline/metabolismABSTRACT
Two series of N9-alkylaminomethyl-, alkylpiperazino-, alkylpiperidino-substituted 1,3-dimethyl-(hexahydropyrimidino)- and (tetrahydropyrimidono)-[2,1-f]-purines were prepared and their physicochemical and pharmacological properties were described. The most active in central nervous system tests were the compounds with phenylpiperazinealkyl substituent i.e. 1,3-dimethyl-2,4-dioxo-9-[N1N4-(phenyl)-piperazinopropyl]-1, 3,6,7,8,9- hexahydropyrimidino-[2,1-f] purine 6a and its butyl and isobutyl homologs 9 and 12. The compounds depressed statistically significantly spontaneous locomotor and amphetamine activity and showed sedative, analgetic and hypothermizing properties.
Subject(s)
Behavior, Animal/drug effects , Central Nervous System Depressants/pharmacology , Purines/pharmacology , Animals , Body Temperature/drug effects , Central Nervous System Depressants/chemical synthesis , Central Nervous System Depressants/toxicity , Drug Evaluation, Preclinical , Magnetic Resonance Spectroscopy , Male , Mice , Motor Activity/drug effects , Purines/chemical synthesis , Purines/toxicity , Rats , Rats, WistarABSTRACT
Synthesis, chemical properties and results of preliminary pharmacological evaluation of several new 9-substituted pyrimidino-[2,1-f]-purines are described. The most interesting was 1,3-dimethyl-2,4,8-trioxo-9-[gamma-N1-(N4-C6H5)-piperazynopropy l]-1,3,6,7-tetrahydro-9H-pyrimidino-[2,1-f]-purine (compound 4a), which exerted strong sedative, hypothermizing and cataleptogenic action and possessed some anti-amphetamine and anti-apomorphine properties.
Subject(s)
Purines/chemical synthesis , Pyrimidinones/chemical synthesis , Amphetamine/pharmacology , Animals , Anticonvulsants , Antidepressive Agents/pharmacology , Apomorphine/pharmacology , Body Temperature/drug effects , Catalepsy/chemically induced , Haloperidol/pharmacology , Lethal Dose 50 , Male , Mice , Motor Activity/drug effects , Purines/pharmacology , Purines/toxicity , Pyrimidinones/pharmacology , Pyrimidinones/toxicity , Rats , Rats, Inbred Strains , Reserpine/antagonists & inhibitors , Spectrophotometry, Infrared , Stereotyped Behavior/drug effectsABSTRACT
Methods of synthesis, chemical properties and results of preliminary pharmacological screening for 8-amino substituted derivatives of caffeine (1-3) and 7,8-disubstituted derivatives of 8-aminotheophylline (8-12) have been described. The compounds show weak sedative and antidepressive activity and some of them (2, 10, 12) also small antinociceptive effect.
Subject(s)
Xanthines/pharmacology , Analgesics , Animals , Anticonvulsants , Apomorphine/antagonists & inhibitors , Body Temperature/drug effects , Chemical Phenomena , Chemistry , Haloperidol/antagonists & inhibitors , Lethal Dose 50 , Male , Mice , Motor Activity/drug effects , Piperazines/antagonists & inhibitors , Psychomotor Performance/drug effects , Rats , Rats, Inbred Strains , Reserpine/antagonists & inhibitors , Xanthines/chemical synthesis , Xanthines/toxicityABSTRACT
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.
Subject(s)
Amino Alcohols/pharmacology , Cardiovascular System/drug effects , Theophylline/analogs & derivatives , Amino Alcohols/toxicity , Animals , Female , Guinea Pigs , Mice , Rats , Rats, Inbred StrainsABSTRACT
7-Aminoxyalkyltheophyllines 4-6 were obtained in good yield by acidolysis or hydrazinolysis of 7-phtalimidoxyalkyltheophyllines 1-3. The structure of obtained compounds was confirmed on chemical routs by preparing typical derivatives (acyl, and oximes) and by UV, IR and NMR spectra.
