Philosophy is "phun"--a celebration in limericks

Raymond Rowe discusses the relationship between science and philosophy.     

P-7521--a new irreversible opioid ligand

In the receptor binding assay, P-7521 was a potent opioid ligand which acted mainly on mu receptor. The relative affinity ratio at mu, delta and kappa sites was 66:8:1. The inhibitory effects of P-7521 were 1868 and 6060 times more potent than morphine on the electrically evoked contractions in guinea pig ileum and mouse vas deferens, respectively and were readily antagonized by naloxone and Mr2266. These results indicate that P-7521 acted on mu receptor in guinea pig ileum and mouse vas deferens. In rabbit vas deferens, the compound had no agonist activity, but could antagonize the inhibitory effect of U-50488 H, a kappa agonist, showing the antagonistic characterization was on kappa receptor. The dissociation of P-7521 binding to opioid receptor were very difficult in mu binding assay and bioassays.     

The chemical composition of "zymosans" from yeasts

The chemical composition of "Zymosanes" (complex cell-wall-polysaccharides), prepared by different methods from Baker's yeast, were analyzed by classical and modern techniques, e.g. GLC and TLC. They are very complex natural products consisting of a basic structure of polysaccharides, which proteins and different lipids are bound to. Higher purified zymosanes seem to be free from nucleic acids and do not contain sialic acid.     

F30385实验治疗血吸虫病的初步研究

实验发现F30385是一个兼具明显杀日本血吸虫童虫与成虫的硝基呋喃丙烯酰胺类的口服药物。小白鼠一次口服F30385的半数致死置为979±98毫克/公斤(P=0.95)。小白鼠感染尾蚴后4-11天,一次口服F30385 11.4毫克/鼠,减虫率高达90-99%,显著比对32天成虫的杀虫作用强。按等毒性剂量用F30385及F30066治疗小白鼠与兔血吸虫病的结果,F30385的疗效比F30066高。7只感染血吸虫病的犬用总剂量为700毫克/公斤的7-14天疗法治疗后,减虫率为95%。动物口服F30385后的毒性反应主要为胃肠道刺激与肾和肝的受损。小白鼠病理观察结果认为,停药后病变均渐恢复。     

Salvinorin A: the "magic mint" hallucinogen finds a molecular target in the kappa opioid receptor

Salvinorin A, a neoclerodane diterpene, is the most potent naturally occurring hallucinogen known and rivals the synthetic hallucinogen lysergic acid diethylamide in potency. Recently, the molecular target of salvinorin A was identified as the kappa opioid receptor (KOR). Salvinorin A represents the only known non-nitrogenous KOR selective agonist. Based on the selectivity of salvinorin A for the KOR, this receptor represents a potential molecular target for the development of drugs to treat disorders characterized by alterations in perception, including schizophrenia, Alzheimer's disease and bipolar disorder.     

P-8502--a new mu selective opioid receptor ligand

The analgesic potencies of 3-[beta-(p-amino)-phenethyl)-9 beta-methoxy-9 alpha-(m-methoxyphenyl)-3- azabicyclo [3,3,1] nonane (P-8502) and 3-[beta-(p-monoester fumarylamido)-phenethyl]-9 beta-methoxy-9 alpha-(m-methoxyphenyl)-3-azabicyclo [3,3,1] nonane (P-8511) were examined. The analgesic ED50 of P-8502 and P-8511 were 55 and 200 micrograms/kg (mice, ip, hot plate), and 30 and 95 micrograms/kg (rat, sc, tail flick), respectively. The duration of the analgesic action of P-8511 (about 4 h) was longer than that of P-8502 (about 1.5 h, rat, sc, tail flick). Binding assay showed that P-8502 had a high ratio of delta/mu, kappa/mu: IC50 (DPDPE)/IC50 (DAGO) = 399; IC50(DAD-LE)/IC50 (DAGO) = 1498; IC50 (kappa)/IC50 (DAGO) = 159. In conclusion, P-8502 appears to be a new mu selective opioid receptor ligand, whereas P-8511 has no such selectivity.     

Papaver bracteatum Lindl.--a new plant source of opiates

Certain strains of P. bracteatum Lindl. are reported to contain in the roots significant quantities of thebaine, which can be used for the production of codeine and other opiates. Results from plants raised from Iranian seeds and grown near London for 4 to 5 years are presented. The botanical and chemical characters correspond closely to those of the active strain Halle III described by Böhm (1970) and enable this plant to be clearly distinguished from the closely related P. orientale L. The thebaine content of the roots was 0.25 % which is much lower than the value of 0.7 to 1.3% reported in Halle III roots. The fruiting tops, however, were also investigated and found to contain significant amounts of thebaine in field conditions. If tops were harvested in the summer and roots in the autumn, about 15 kg thebaine per hectare should be produced from our strain grown in the conditions described. This compares favourably with about 1 kg alkaloids per hectare from Turkish opium production or even the 3 kg per hectare from the high yielding Indian farms.     

Stabilisation of calstabin2--a new approach in sudden cardiac death

Calstablin2 stabilises the ryanodine receptor (RyR2), preventing aberrant activation of the channels during the resting phase of the cardiac muscle. Loss of this stabilisation may be associated with cardiac arrhythmias, the sudden death occasionally observed in people with structurally normal hearts, as well as the atrial fibrillation in heart failure. Calstabin2-deficient mice have structurally normal hearts but exhibit exercise-induced cardiac ventricular arrhythmias that cause sudden death. In arrhythmias, the calstabin2 stabiliser JTV519 did not prevent arrhythmias in calstabin2-/- mice, but reduced the arrhythmias in calstabin2+/- mice, illustrating the antiarrhythmic potential of stabilising calstablin2. Familial polymorphic ventricular tachycardia in humans has been linked to missense mutants in the hRyR2 gene. In HEK293 cells, these RyR2 mutants showed less binding of 35S-calstabin2 than the wild type, indicating a reduced binding affinity. In human atrial fibrillation and heart failure, where there is excessive disassociation of calstabin2 from the RyR2 receptor in vitro, JTV519 is able to reverse this. In conclusion, calstabin2 is an important new target in sudden cardiac death associated with structurally normal hearts, and in the treatment of atrial fibrillation and heart failure.     

The pharmacology of epanolol (ICI 141292)--a new beta 1-selective adrenoceptor partial agonist

The clinical benefit of beta-adrenoceptor partial agonists is still debated. To clarify the situation, epanolol, ICI 141,292 [N-[-2-(3-o-cyanophenoxy-2-hydroxypropylamino)ethyl]-4- hydroxyphenylactamide], has been developed to assess the role of modest beta-adrenoceptor partial agonist activity in humans. Animal studies have shown that epanolol is a potent beta-adrenoceptor partial agonist with a greater affinity for beta 1- than beta 2-adrenoceptors. In vitro, the PA2 values obtained for espanolol at atrial and tracheal beta-adrenoceptors were 8.42 and 6.33, respectively (isoproterenol as agonist), giving a selectivity ratio of 123. The potency was studied in vivo in the dog, where it was also shown that as an antagonist at the cardiac beta 1-adrenoceptor, it was 18 and 40 times more potent than atenolol and practolol, respectively. Espanolol has less partial agonist activity in the rat than pindolol, but more than practolol. In this species, it is also a classical partial agonist, exhibiting agonist activity at all beta-adrenoceptor blocking doses. This is in contrast to pindolol, which caused predominantly beta-adrenoceptor blockade at low doses and partial agonist activity at higher doses. These differences were confirmed in haemodynamic studies in the dog. In contrast to many other partial agonists, the partition coefficient, log P, of epanolol in octanol and water is low (0.92).     

Examination of the hallucinogen 2,5-dimethoxy-4-methylamphetamine

Physical characteristics are reported for a tablet form of a new hallucinogenic drug previously circulating in the USA under the name “STP”. High resolution mass, nmr, ultraviolet and infrared spectrometric evidence, which identify the extracted base as 2,5-dimethoxy-4-methylamphetamine, and its chromatographic behaviour, are compared with the experimental compound “DOM”. Polymorphic modifications exhibiting distinct solid phase infrared spectra have been studied by X-ray diffraction and by differential calorimetry. Animal behavioural tests indicate that the psychotomimetic activity of the base is comparable with mescaline but up to 50 times more potent.