摘要:

AbstractThe quinazolinedione derivative ketanserin was studied in many known and newly introduced tests to obtain its detailed pharmacological profile. Ketanserin was a potent, orally very effective antagonist of endogenous serotonin (5‐HT): 0.15 mg/kg (ED50s.c. and p.o.) protected rats from the gastric lesions induced by the mast cell activator compound 48/80. Many other in vivo observations, such as antagonism of tryptamine‐induced cyanosis in rats (ED50s.c., 0.056 mg/kg), inhibition of mescaline‐induced head twitches in rats (ED50s.c., 0.097 mg/kg), and inhibition of 5‐HT‐induced effects in various species, revealed the potent antagonist activity of ketanserin on vasoconstrictor and bronchoconstrictor actions of serotonin. When compared to other compounds with 5‐HT‐antagonist activity, the pharmacological profile of ketanserin corresponds to that of a potent, peripherally acting serotonin antagonist with weak associated α‐adrenergic blocking and antihistamine activity. In addition, binding experiments and studies on isolated tissues and platelets disclosed the high selectivity of ketanserin's serotonin antagonism. Serotonin S2‐receptors of the rat frontal cortex were labeled by low concentrations of ketanserin (Ki= 0.39 nM), and affinity of drugs for S2‐receptors highly correlated with their activity against serotonin‐induced contractions of blood vessel preparations (e.g., of the rat caudal artery, A2‐value of ketanserin: 0.83 nM) and serotonin‐induced platelet aggregation. In these experiments, ketanserin was devoid of serotonin! ‐binding, of agonist activity on vascular smooth muscle, of inhibition of 5‐HT uptake into platelets, and of 5‐HT antagonism on gastrointestinal smooth muscle. The absence of all these secondary activities is pharmacologically characteristic for ketanserin when compared to known serotonin‐antagonists. On the basis of this profile of pure and selective serotonin S2‐antagonism, ketanserin was studied in experimental hypertension and in many spontaneous and induced circulatory dysfunctions. A prolonged antihypertensive effect can be obtained with ketanserin in the absence of distinct compensatory mechanisms. Vascular dysfunction can start at low, sensitizing concentrations of serotonin and be almost completely corrected by ketanserin, despite the involvement of other mediators. Ketanserin is a very effective antagonist of the mixture of vasoactive substances released by aggregating platelets. In experimental thrombosis, sustained ketanserin treatment prevents the impairment of blood flow and the associated organ deficiency. When deviations from normal hemorrheology are long‐standing, as in aged spontaneously hypertensive dogs, acute ketanserin administration is distinctly antihypertensive and reduces hemorrheological abnormalities. At the conclusion of these extensive studies, serotonin appears to act at peripheral S2‐receptors as the primary path

ISSN:0272-4391    

DOI:10.1002/ddr.430060402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractHR 375, a 3‐(4‐(3‐(4‐fluorobenzoyl)‐propyl‐piperazino‐l‐yl‐isoquinolino‐ hydrochloride is a new compound with marked effects in tests of predictive value for neuroleptic activity. Its pharmacological profile is different from classical neuroleptics. HR 375 has inhibitory activity in apomorphine‐induced climbing, amphetamine aggregation toxicity, Sidman avoidance, and amphetamine‐induced hypermotility. On the other hand, only weak activity is seen in antagonizing amphetamine‐induced stereotypy, apomorphine‐turning, and apomorphine emesis. It does not include catalepsy in rats and cynomolgus monkeys even in high doses. Also, its sedative or muscle relaxant properties are weak and short‐lasting. The psychopharmacological profile of HR 375 indicates a split between its effects on the mesoli

ISSN:0272-4391    

DOI:10.1002/ddr.430060403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractCGS 9895 is a pyrazoloquinoline closely related to the benzodiazepine agonist CGS 9896 and the benzodiazepine antagonist CGS 8216. In anxiolytic test procedures, this compound generalizes to CGS 9896 discriminative stimuli, produces an increase in punished responding, and partially antagonizes pentylenetetrazol discriminative stimuli. This anxiolytic activity is not, however, accompanied by any detectable sedation or muscle relaxation. CGS 9895 does not impair rotorod performance or reduce motor activity and does not potentiate ethanol‐induced rotorod impairment or hexobarbital‐induced sleeptime. This compound does not generalize to diazepam discriminative stimuli, suggesting a difference between the internal stimuli produced by this drug and those of diazepam. Only weak anticonvulsant activity is noted with CGS 9895. In addition to the benzodiazepine agonist effects of this compound, CGS 9895 is capable of antagonizing the rotorod deficit produced by diazepam. It also selectively antagonizes the sedative effect of diazepam in the conflict procedure without reducing the anxiolytic effect of diazepam. Overall, CGS 9895 exhibits a novel combination of benzodiazepine agonist and antagonist properties. This unique profile suggests that CGS 9895 may be a clinically useful, novel anxiolytic ag

ISSN:0272-4391    

DOI:10.1002/ddr.430060404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractPropentofylline (HWA 285) [3‐methyl‐1‐(5′‐oxohexyl)‐7‐propylxanthine] is in in vitro experiments a good inhibitor of cAMP and cGMP phosphodiesterases in the rat brain and cerebral microvessels. In in vivo experiments it modulates cAMP and cGMP systems and GABA concentration in four examined structures of rats: cortex, hypothalamus, cerebellum, and striatum. Propentofylline (5 mg/kg i.v.) doesn't influence levels of cerebral energy reserves in normal rats but prevents to a significant degree some of the changes in metabolite levels caused by anoxia (30 s of nitrogen breathing). This antianoxic effect occurs at 5 min and disappears 20 min after administaration of the drug. Caffeine (5 mg/kg i.v.) shows a trend toward further aggravation of anoxia. The modulating effect of propentofylline on cAMP and cGMP systems, GABA levels, and especially cererbral enery metabolism in anoxia is possibly related to the potential therapeutic effect

ISSN:0272-4391    

DOI:10.1002/ddr.430060405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractFollowing the bilateral occlusion of common carotid arteries in gerbil, an increase in water content and sodium/potassium ratio as well as the inhibition of Na+‐K+‐ATPase was found. The xanthine derivative propentofylline (HWA 285) [3‐methyl‐1‐(5‐oxohexyl)‐7‐propylxanthine] given either before or after cerebral ischemia attenuated the development or postischemic brain swelling and the increase in sodium/potassium ratio and prevented the postischemic reduction of Na+‐K+‐ATPase activity. It is concluded that the action of propentofylline on brain edema during ischemia is mediated aside from other possible mechanism(s), by the influence of the drug on Na+

ISSN:0272-4391    

DOI:10.1002/ddr.430060406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractCGS 10078B is a potent orally effective antihypertensive agent with β‐adrenergic antagonist as well as other vasodilatory mechanisms. In spontaneously hypertensive rats, CGS 10078B (3 and 30 mg/kg, p.o.) caused rapid and significant dose‐related reductions in blood pressure that were sustained at 24 hr and accompanied by moderate reductions in heart rate. In conscious hypertensive dogs, CGS 10078B (3 mg/kg, p.o.) produced decreases in blood pressure that were of greater magnitude than those obtained with propranolol and better maintained than those obtained with nifedipine at comparable dosage. Radioligand binding assays indicated that CGS 10078B antagonizes α1‐, β1‐, and β2‐adrenoceptors and inhibits nitrendipine binding at sites associated with Ca++channels. These biochemical results correlate well with in vitro cardiovascular studies, demonstrating that CGS 10078B possesses antagonist activity at β1‐receptors (guinea pig left atria), β2‐receptors (guinea pig trachea), β1‐receptors (rabbit aorta), and voltage‐sensitive Ca++channels (responses to K+or Ca++in rabbit aorta), and on Ca++uptake and retention (45Ca in rabbit aorta). In vivo studies with dogs treated with CGS 10078B (30 mg/kg, p.o.) also identified nonselective β‐antagonism and no interference with orthostatic reflexes. In summary, the multiple modes of action of CGS 10078B may afford a distinct clinical advantage in th

ISSN:0272-4391    

DOI:10.1002/ddr.430060407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractIndomethacin was studied for its effects on three indices of gastric mucosal integrity in anesthetized cats. Following intragastric administration of the compound under conditions of constant stomach acidity and electrolyte concentrations, the transgastric potential difference declined in a gradual, linear fashion during the 210 min of the experimental period. These changes, which were dose related over the range of 1.25‐5 mg/kg of indomethacin, were accompanied by increased concentrations of luminal pepsin and blood. The results suggest that the transgastric potential difference is a sensitive indicator of gastric mucosal integrity under the conditions of this stud

ISSN:0272-4391    

DOI:10.1002/ddr.430060408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractTolerability of CGP 4718 A (sercloremine), a 4‐(5‐chloro‐2‐benzofuranyl)‐1‐methyl‐piperdine, as well as the effects on target symptoms in 22 hospitalized depressed patients, were investigated in an open, multicenter study. In daily doses of 50 to 150 mg, the compound was well tolerated. There were no changes in cardiovascular parameters (blood pressure, ECG) nor were there changes in laboratory values that could be considered of clinical relevance. Of concern, however, were sleep disturbances, which appeared to be aggravated in the majority of treated patients. There were only a few other side‐effects that could be related to the drug treatment, and they were mostly mild and transitory. The therapeutic effects of CGP 4718 A, as judged by the changes in total Hamilton depression rating scores and global assessement, indicated beneficial action of the drug on the core symptoms of depression (except sleep disturbances). The therapeutic effect appeared to be dose‐related and particularly marked in neurotic and reactive depressions. These findings, in line with the predictions made on the basis of preclinical animal studies, encourage further clinical testing

ISSN:0272-4391    

DOI:10.1002/ddr.430060409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

Abstract1‐(3‐Chlorophenyl)‐3‐diethylcarbamoyl‐1 H‐1,2,4‐triazole (CP‐32,961) inhibited [3H]diazepam binding to rat cortical membrances and [3H]flunitrazepam binding to mouse brain in vivo. Its inhibition of the binding of [3H]Ro 15‐1788 (benzodiazepine receptor antagonist) to these membranes was not facilitated by added GABA; CP‐32,961 exhibited a GABA ratio of 0.84 compared to 2.44 for diazepam. Cerebellar cyclic GMP content in rats was raised by CP‐32,961, which also further elevated the increased cyclic GMP levels induced by isoniazid. These neurochemical actions are similar to those shown by ethyl β‐carboline‐3‐carboxylate (β‐CCE) and suggest that CP‐32,961 is a benzodiazepine receptor antagon

ISSN:0272-4391    

DOI:10.1002/ddr.430060410

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY

摘要:

AbstractThe responses to adenosine and its analog, inosine, were compared in isolated rings of canine small renal arteries (0.5–1.3 mm o.d.). The rings were not contracted prior to nucleoside administration in order to detect any contraction response due to the nucleoside itself. Relaxation responses were elicited by progressively increasing the nucleoside concentration in the bathing medium. The maximal response (Rmax) was expressed as a percentage of the decrease in isometric tension. The ED50 for adenosine and inosine was 0.18 ± .002 μM and 202 ± 44 μM, respectively (P<0.05) The Rmaxfor inosine was significantly less (P<0.05) than that for adenosine, with a mean ratio of adenosine Rmaxinosine Rmaxof 1.47 ± 0.2. The results of these experiments indicated that adenosine and inosine directly relax isolated small renal arterial rings, although the classic in situ renal response to adenosine is increased resistance. Also, the relaxing action of adenosine, but not inosine, is significantly attenuated by 10 μM aminophylline. Further, renal arterial rings exhibit a greater sensitivity to adenosine than that previously reported for canine coronary artery rings, while the response to inosine is virtually id

ISSN:0272-4391    

DOI:10.1002/ddr.430060411

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1985

数据来源: WILEY