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The synthesis of (+/-)-1-ethylenedioxy-trans-2-(beta-R,S-hydroxypropyl)-3-(beta-acetoxyethyl)cyclopentane (IV), starting from (+/-)-1-ethylenedioxy-trans-2-propargyl-3-(beta-hydroxyethyl)cyclopentane (I) by indirect hydration with mercuric acetate and hydrogen sulphide, is reported.
The polymorphic behavior of three series of tris-homoacyl (C14:0, C16:0 and C18:0) cyclopentane-1,2,3-triol analogs of the natural saturated triglycerides has been studied using differential thermal analysis, Fourier transform infrared spectroscopy, and X-ray diffraction. It was found that the triglyceride analogs derived from the 1,2,3/0 and 1,2/3 cyclopentanetriols exhibit different polymorphic behavior than that of the natural triglycerides. The analogs derived from 1,3/2 cyclopentanetriol, however, were found to parallel the polymorphic behavior of the natural triglycerides quite closely. This polymorphic behavior is discussed in terms of the different configurations which the chains assume in each of the triglyceride analogs.
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Ozonolysis of 6-oxo-PGF1alpha, 11,15-diacetate, methyl acetal, methyl ester followed by oxidative workup and treatment with diazomethane gave 3-acetoxy-5-hydroxy-2-(methoxycarbonyl) cyclopentane acetic acid, gamma-lactone and dimethyl 3-acetoxy-5[[-(methoxycarbonyl)valeryl]oxy]-1,2-cyclopentane dicarboxylate as two of the major products. The mass spectral properties of the latter compound were identical with those previously published by other investigators.
This study was undertaken with the aim of determining whether the postsynaptic alpha-adrenergic receptor population of the cat urethra differed from that of other isolated tissues (rabbit aorta and rat vas deferens) and if so the possibility of selectively affect these receptors. For this purpose the substances 2-methylammonio-1-(spiro[cyclopentane-1,1'-indene]-3'-yl)ethanol (KABI 2023), noradrenaline (NA) and dopamine (DA) were used. KABI 2023 and NA acted as full agonists on all three tissues investigated. DA was a full agonist on the vas deferens but was almost inactive on urethra. The contractile response of urethra to KABI 2023 was of an alpha-adrenergic nature, as it could be blocked with phentolamine. Compared with NA, KABI 2023 showed a 10 times higher selectivity for the receptors of urethra than for those of aorta. Affinity constants (log KB) for phentolamine and haloperidol with use of the various agonists were estimated. The affinity of phentolamine was found to be significantly different when using NA and KABI 2023 as agonists on the urethra but not on the aorta. Corresponding findings were obtained with haloperidol. On the vas deferens a greater difference in log KB values than that on the urethra was found. On the basis of the results, it is suggested that the population of postsynaptic alpha-adrenoceptors in the urethra (cat) differs from that in the aorta (rabbit). On the vas deferens a heterogenicity of postsynaptic receptors seem to exist which makes the interpretation of the results more difficult on this organ. In the presence of phentolamine and haloperidol the maximum responses to NA were potentiated on the aorta and vas deferens, but not on the urethra. Investigations to evaluate this difference are now in progress.
The acid-catalyzed isomerization of the diglyceride analog (1,2,3/0)-1,2-dipalmitoylcyclopentane-1,2,3-triol has been used to generate syn-syn-1,3-diacyl-cyclopentane-1,2,3-triol, a required intermediate in the synthesis of a symmetrical all-cis-1,2,3/0-2P cyclopentanoid phosphatidic acid analog. The all-cis cyclo-phosphatidic acid analog has therefore been obtained in the free acid form and as the diphenyl ester, dimethyl ester, and dipotassium salt derivatives. The compounds have been characterized by microanalysis and spectroscopic methods. The 1,2,3/0-2P analog is now available for comparative studies with the corresponding all-trans cyclophosphatidic acid (1,3/2-2P).
A new series of phosphatidic acid analogs has been synthesized in which the glycerol moiety of diacylglycerophosphoric acid is replaced by each of the three isomeric cyclopentane-1,2,3-triols (1,3/2, DL-1,2/3, and 1,2,3/0). Of the seven possible configurational and positional phosphatidic acid analogs of this series, five isomers have been obtained and characterized by spectroscopic methods and microanalysis. Four of the five isomers are 1-(or 3-)phosphoryl derivatives, while the fifth is a 2-phosphate. The analogs were prepared in configurationally pure form by unequivocal synthetic procedures involving selectively blocked intermediates: acyl migration was avoided by the use of mild deblocking procedures. The anhydrous lipid products, all of which are dipalmitoyl esters, are solids indefinitely stable at room temperature in the free acid or potassium salt form; they have chromographic mobility and melting points similar to dipalmitoyl glycerophosphoric acid the dipotassium salts bind water of hydration tenaciously, remaining hydrated after drying in vacuo at 100 degrees C. NMR spectra of dimethyl esters of some of the analogs show nonequivalence of the two methyl groups, consistent with the diastereotopic nature of those groups. In addition to their intrinsic interest as conformationally restricted acidic lipids, the analogs are now available as starting materials for the synthesis of the more complex acidic and amphoteric lipids required for our exploitation of these cyclopentanoid analogs as unique probes for the study of lipid-lipid and protein-lipid interactions.
A gas chromatographic method for the plasma assay of the anticonvulsant, sodium valproate, is described. Derivatization is not necessary. 200 microliter plasma are required for a single estimation. The method involves a chloroform extraction of valproate and the internal standard, cyclopentane carboxylic acid, from acidified plasma. Gas-liquid chromatography using the stationary phase 10% SP-216-PS gives complete separation of valproate and the internal standard in eight minutes. The limit of detection is 20 mumol valproate/1 plasma (equivalent to 40 pmol on column). This is well below the lower therapeutic plasma level. The between-run precision of the method indicates a variation for each sample within+/-3% of its mean value.
Some aromatic prostaglandin analogs, having a benzene (2a, 2b) and a dimethoxybenzene (1) ring in place of the cyclopentane moiety, have been synthesized. The key intermediates in the syntheses were lactols 9 and 5, which were elaborated to the final products via two olefination reactions. Compound 2b was twice as potent as phenylbutazone and nine times as potent as aspirin in inhibiting prostaglandin synthetase activity.
A number of analogs of the tripeptide L-prolyly-L-leucylglycinamide (1) were synthesized and evaluated in the Dopa potentiation and oxotremorine antagonism tests. The replacement of the glycinamide residue with either the glycine methylamide, glycine, aminoacetonitrile, amino-2-propanone, semicarbazide, or beta-alaninamide residues resulted in a loss of activity in both tests. A 1:1 mixture of L-prolyl-L-leucyl-(-)-thiazolidine-2-carboxamide (8) and L-prolyl-L-leucyl-(+)-thiazolidine-2-carboxamide (9) showed marked activity in the Dopa potentiation test but was unable to antagonize the tremors induced by oxotremorine. L-Prolyl-L-leucyl-L-prolinamide (11), on the other hand, was active in the oxotremorine antagonism test but inactive in the Dopa potentiation test. The replacement of the pyrrolidine ring of 1 with either a thiazolidine or cyclopentane ring system caused a loss of activity. The cyclopentanecarboxylic acid analogue 13, however, was found to have moderate activity in the serotonin potentiation test.
Proton magnetic spectra have been recorded for muscarine and two biologically active cyclopentane analogues. In order to observe homonuclear intramolecular nuclear Overhauser effects, the -N+(CH3)3 signal was irradiated and increases in integrated intensities for other key signals in the molecule were observed. The results indicate that the quaternary side chain in these compounds is in an extended conformation in aqueous solution.
The synthesis is described of a series of acylhydroxyalkanoic acids which embody structural modifications of that class of secoprostaglandins which are formally derived from the natural substances by scission of the cyclopentane ring between carbon atoms 11 and 12. These analogues have been tested for their ability to stimulate cAMP formation in the mouse ovary, a characteristic action of the (E)-prostaglandins, and for their ability to bind to the rat lipocyte prostaglandin receptor. Certain members of the series that most closely resemble the prostaglandins in structure (e.g., 8-acetyl-12-hydroxyheptadecanoic acid) markedly stimulate cAMP formation at concentrations in the pharmacological range and show a significant affinity for the prostaglandin receptor. Conversely, these compounds are not substrates for prostaglandin 15-hydroxydehydrogenase which catalyzes a major reaction in the biological deactivation of the prostaglandins.
The hairpin conformational hypothesis has been proposed to rationalise much of the structure-activity and receptor-binding data which have accumulated for the prostaglandin (PG) hormones. The hairpin conformation, thought to be necessary for PG activity, requires that the alpha- and omega-chains of the molecule be extended and in parallel alignment, separated by a van der Waals contact distance for the full length of the chains, with the ends of the chains approximately 5.5 A apart. The similarity between the structures of the thromboxanes (TXs) and the PGs suggests that the profile of activity of TXs, like that of PGs, centres on subtle conformational variation of the hairpin geometry. Thromboxane B2 (TXB2) is a stable hydrolysis product of a highly reactive, short-lived intermediate, thromboxane A2 (TXA2), which is formed from the prostaglandin endoperoxide (PGH2) as indicated in Fig. 1. An examination of molecular models of TXA2 and TXB2 suggests that the structural differences between the ring moieties may have much less influence in altering the side-chain conformation of TXs than do substitutents on the relatively more flexible cyclopentane ring of a PG molecule. We report here the first diffraction analysis of a thromboxane structure and note that the molecular conformation is not hairpin shaped.
The antibiotic whose biosynthesis is determined by the SCP1 plasmid of Streptomyces coelicolor A3(2) has been characterized as the recently described methylenomycin A (2-methylene-cyclopentan-3-one-4,5-epoxy-4,5-dimethyl-1-carboxylic acid).
1 The isolated spinal cord of the frog (Rana pipiens) was used to examine the structural requirement for the activity of neutral amino acids. The potencies of the aliphatic amino acids, gamma-aminobutyric acid (GABA), beta-alanine and glycine were compared with the potencies of conformationally restricted cyclopentane and cyclohexane amino acid analogues. Both motoneurone hyperpolarizing and primary afferent depolarizing activity were examined in this study. 2 On motoneurones beta-alanine was the most potent aliphatic amino acid and glycine the least potent. Of the substituted aminocyclopentane carboxylic acids, that compound with a separation of amino and carboxylic acid groups closest to that of the extended GABA molecule (4.74 A) had a potency similar to GABA. As the separation decreased the hyperpolarizing activity fell off rapidly. The substituted aminocyclohexane carboxylic acids were generally inactive even at a concentration of 10 mM. 3 Strychnine blocked the motoneurone hyperpolarizing responses to all compounds with a distance between the amino and carboxylic acid groups of 3.66 A or less, but did not block the response of compounds with a distance of 4.08 A or greater. Picrotoxin and bicuculline antagonized all the responses to varying degrees and therefore were of little value in characterizing the responses. 4 On the primary afferents GABA was the most potent aliphatic amino acid and glycine the least potent. The substituted aminocyclohexane carboxylic acids were generally inactive on primary afferents. The response of the substituted aminocyclopentane carboxylic acid whose separation of amino and carboxylic acid groups was closest to that of the extended GABA molecule was most similar to the GABA response. However, (+/-)-cis-3-aminocyclopentane-carboxylic acid (separation=4.08 A),which mimicked the action of GABA on motoneurones, closely mimicked the depolarizing action of beta-alanine on primary afferents. 5 The findings suggest that the hyperpolarizing GABA receptor on motoneurones will accept a molecule whose amino and carboxylic acid groups are separated by a distance of 4.08 A or greater while the glycine receptor will accept a compound with a distance of 3.66 A or less. The depolarizing GABA receptors on primary afferents appear to be more selective since they are not activated by (+/-)-cis-3-aminocyclopentane carboxylic acid (separation = 4.08 A), while the motoneurone receptors are.
1. The effects of some muscarinic antagonists, namely, N-ethyl-2-pyrrolidylmethyl-cyclopentylphenyl glycollate (PMCG), N-methyl-4-piperidyl-phenylcyclohexyl glycollate (PPCG, racemate and R and S enantiomers) and 4'-N-methyl-piperidyl-1-phenyl-cyclopentane carboxylate (G3063) on organophosphate (sarin, soman)- and carbamate (neostigmine)-induced twitch augmentation have been studied in cat soleus muscle. 2. The results of a preliminary study comparing the potency of sarin and soman in inhibiting the acetylcholinesterase activity of muscle in relation to the effect on the maximal twitch response indicated that there is not a simple relationship between degree of enzyme inhibition by these drugs and alteration of muscle function. 3. The muscarinic antagonists studied were capable of preventing or reversing sarin-, soman- or neostigmine-induced twitch augmentation. Doses sufficient to give complete protection from the effects of the anticholinesterase agents had little or no effect on the twitch response of normal muscle. 4. The protective action of these muscarinic antagonists is dose-dependent but independent of known antagonist actions at muscarinic receptors. 5. The effects of some local anaesthetics (lignocaine, prilocaine, cinchocaine, procaine) and other membrane stabilizers (quinine, ketamine, chlorpromazine, triflupromazine) were compared with those of the muscarinic antagonists in an attempt to elucidate the mode of action of these acetylcholine antagonists. The evidence is insufficient to exclude the involvement of a membrane stabilizing action.
1. The relative potencies of a number of analogues of L-glutamate as excitants of thalamic neurones in the rat have been compared. The most powerful compounds were kainate, ibotenate and (+/-)cis-1-amino-1,3-dicarboxycyclopentane. The D- and L-isomers of glutamate and aspartate were also compared. Whereas D-glutamate is approximately one-half as active as the L-form, D-aspartate is more potent than L-aspartate. 2. Computer analysis has indicated that ibotenate and cis-1-amino-1,3-dicarboxy-cyclopentane have relatively fixed and similar C alpha-N, Comega-N and C alpha-Comega interatomic distances which can also be achieved by glutamate in certain conformations of the molecule, but not by aspartate. 3. Parallel examination of the antagonists glutamate diethylester and D-alpha-aminoadipate has shown that the former preferentially reduces L-glutamate effects while the latter blocks the actions of other amino acid excitants more readily than those of L-glutamate. 4. The evidence is consistent with the hypothesis that at least two populations of neuronal receptors for the excitatory amino acids exist.
A mutant of Bacillus subtilis synthesizes a variety of omega-alicyclic fatty acids when fed with the respective alicyclic carboxylic acids. These fatty acids are: omega-cyclopropane, omega-cyclobutane, omega-cyclopentane, omega-cyclohexane, and omega-cyclohexene fatty acids. These unusual fatty acids did not lead to an inhibition of growth at 37 degrees C and pH 7. The selective advantage of these fatty acids under extrene conditions was studied in comparison with the acidophilic, thermophilic bacterium B. acidocaldarius, which normally contains a high proportion of omega-cyclohexane fatty acids.