Disposition kinetics of cyclohexanone in beagle dogs.
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Animals↗
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Spectral transmission and short-wave absorbing pigments in the fish lens--I. Phylogenetic distribution and identity.
Fish lens transmission was found to vary depending on the type and concentration of short-wave absorbing compounds present within the lens. Pigments extracted from lenses of ten species were identified as mycosporine-like amino acids (mainly palythine, palythene and asterina-330, lambda maxs around 320-360 nm) which are also thought to be present in the majority of the 120 species examined here. A novel mycosporine-like pigment with lambda max 385 nm was isolated from the lens of the flying fish, Exocoetus obtusirostris, while lenses of several closely related tropical freshwater species were found to have high concentrations of the tryptophan catabolite 3-hydroxykynurenine (lambda max 370 nm). The type of lens pigment a species possesses and its concentration depends upon both the animal's phylogenetic group and its "optical niche".
Animals↗
ATP:streptomycin 6-phosphotransferase.
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Cyclohexanols↗
The synthesis of prostaglandin analogs containing hydroxycyclohexenyl rings.
The synthesis of prostaglandin analogs incorporating the 3-hydroxycyclohexenyl moiety in place of the natural C13-C20 side-chain has been accomplished via copper-assisted conjugate addition of the cycloalkenyllithium 2 to the cyclopentenous intermediates 4, 7 and 10.
Animals↗
Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs.
Numerous cannabinoids have been synthesized that are extremely potent in all of the behavioral assays conducted in our laboratory. An important feature in increasing potency has been the substitution of a dimethylheptyl (DMH) side chain for the pentyl side chain. Our previous studies have shown that (-)-11-OH-delta 8-THC-dimethylheptyl was 80-1150 times more potent than delta 9-THC. Stereospecificity was demonstrated by its (+)-enantiomer which was more than 1400-7500 times less potent. A related series of DMH cannabinoid analogs has recently been synthesized and preliminary evaluations reported here. (-)-11-OH-delta 9-THC-DMH was found to be equipotent with (-)-11-OH-delta 8-THC-DMH. The aldehyde (-)-11-oxo-delta 9-THC-DMH was 15-50 times more potent than delta 9-THC. Surprisingly, (-)-11-carboxy-delta 9-THC-DMH was also active, being slightly more potent than delta 9-THC. In the bicyclic cannabinoid series, the length and bulk of the side chain were found to be equally important. Aminoalkylindoles, which are structurally dissimilar from classical cannabinoids, have been found to exhibit a pharmacological profile similar to delta 9-THC. Though not extremely potent in vivo, they appear to represent an entirely new approach to studying the actions of the cannabinoids. The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.
Analgesics↗
Pharmacological evaluation of halogenated delta 8-THC analogs.
-(-)-5'-Bromo-delta 8-THC, (-)-5'-trifluoromethyl-delta 8-THC, (-)-5'-iodo-delta 8-THC, (-)-5'-fluoro-delta 8-THC, (-)-11-fluoro-delta 8-THC and (-)-2-iodo-delta 8-THC were synthesized and evaluated in male ICR mice for their effects on sedation, temperature, catalepsy and antinociception following intravenous injection. The analogs were also tested for relative affinities for cannabinoid binding sites derived from rat cortex membranes, using [3H] CP-55,940 as the tritiated ligand. The results showed that the 5'-bromo, 5'-iodo and 5'-trifluoromethyl analogs were 2-40 times more potent than (-)-delta 8-THC in all biological tests, while the 5'-fluoro and 11-fluoro derivatives were less active. With the 2-iodo analog, a 12-fold separation was observed between antinociception and sedation, pointing to the importance of the side chain orientation in determining cannabinoid activity and to the possible involvement of more than one cannabinoid receptor site. The pharmacological data closely paralleled the data obtained from the binding assay.
Analgesics↗
Pharmacological evaluation of iodo and nitro analogs of delta 8-THC and delta 9-THC.
One aspect of cannabinoid structure-activity relationships (SARs) that has not been thoroughly investigated is the aromatic (A) ring. Although halogenation of the side chain enhances potency, our recent observation that iodination of the A ring also enhanced activity was surprising. The purpose of this investigation was to establish the steric and electrostatic requirements at these sites of the cannabinoid molecule via molecular modeling, while determining pharmacological activity. Molecular modeling was performed using the Tripos molecular mechanics force field and the semiempirical quantum mechanical package AM1. The Ki values for novel cannabinoids were determined in a [3H]CP-55,940 binding assay and ED50 values generated from four different evaluations in a mouse model. The present studies underscore the increase in potency produced by a dimethylheptyl (DMH) side chain. Trifluoro substitutions on the pentyl side chain, or bromination of the DMH side chain, had little effect on the pharmacological activity. Any substitution at the C4 position of the aryl ring resulted in a loss of activity, which appears to be due to steric hindrances. Nitro, but not iodo, substitution at the C2 position essentially produces an inactive analog, and the drastic alteration of the electrostatic potential appears to be responsible. The altered pharmacological profile of the 2-iodo analog seems to be related to an alteration in the highest occupied molecular orbital because there is no alteration in the electron density map compared to delta 8-tetrahydrocannibinol.
Analgesics↗
Development of behavioral tolerance to delta 9-THC without alteration of cannabinoid receptor binding or mRNA levels in whole brain.
The effect of repetitive administration of delta-9-tetrahydrocannabinol (delta 9-THC) in mice on behavioral and biochemical tolerance was determined in this study. Mice were injected twice daily with 10 mg/kg delta 9-THC for 6.5 days. On day 8, spontaneous activity was assessed or whole-brain homogenates were prepared for the cannabinoid receptor binding and mRNA studies. Although a twenty-sevenfold tolerance to delta 9-THC was observed in the behavioral assay, there was no significant alteration in receptor binding or mRNA levels.
Animals↗
Intrastriatal injection of cannabinoid receptor agonists induced turning behavior in mice.
When injected unilaterally into the mouse striatum, cannabinoid agonists such as Win 55212-2 (1-100 ng/mouse), CP 55940 (0.1-50 ng/mouse), and anandamide (0.5-50 ng/mouse), the putative endogenous ligand of CB1 receptor, dose-dependently induced turning behavior. SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H- pyrazole-3-carboxamide hydrochloride], the selective antagonist of CB1 receptor, antagonized the three cannabinoid receptor agonists-induced turning with similar ED50s (0.13-0.15 mg/kg, IP). Spiroperidol (a D2 receptor blocker), (+)-SCH 23390 (a D1 receptor blocker), or prior 6-OHDA lesions of the striatum blocked Win 55212-2- and CP 55940-induced turning, thus suggesting the involvement of DA transmission in cannabinoid-induced turning. Taken together, these findings reinforce the notion of a cannabinoid receptor-mediated control of nigrostriatal function.
Analgesics↗
Downregulation of rat brain cannabinoid binding sites after chronic delta 9-tetrahydrocannabinol treatment.
Specific cannabinoid receptors have been recently described in extrapyramidal and limbic areas and presumably might mediate the effects of marijuana exposure on behavioral processes related to those areas. In this work, we examined whether cannabinoid receptors exhibit downregulation as a consequence of the chronic exposure to delta 9-tetrahydrocannabinol (THC), which might explain certain tolerance phenomena observed in relation to motor and limbic effects of marijuana. To this end, we first characterized the binding of cannabinoid receptors, by using [3H]CP-55,940 binding assays, in the striatum, limbic forebrain, and ventral mesencephalon of male rats, and, second, we measured the density and affinity of those receptors in these brain areas after 7 days of a daily treatment with THC. Development of a tolerance phenomenon was behaviorally tested by using an open-field technique. Results were as follows. The three areas studies presented specific and saturable binding for the cannabinoid ligand, as revealed by their corresponding association and dissociation curves, displacement by THC, saturation curves, and Scatchard plots. A chronic treatment with THC produced the expected tolerance phenomenon: The decrease caused by an acute dose in spontaneous locomotor (49.4%) and exploratory (59.7%) activities and, mainly, the increase in the time spent by the rat in inactivity (181.7%) were diminished after 7 days of daily treatment (39.4, 40.4, and 31.7%, respectively). This tolerance was accompanied by significant decreases in the density of cannabinoid receptors in the striatum and limbic forebrain, the areas where nerve terminals for nigrostriatal and mesolimbic dopaminergic systems, respectively, which play an important role in those processes, are located.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Blockade of cannabinoid-induced antinociception by naloxone benzoylhydrazone (NalBZH).
We have recently shown that the antinociceptive effects, but not other behavioral effects of the intrathecally administered, but not intracerebroventricularly administered, cannabinoids, are blocked by the kappa antagonist, nor-binaltorphimine. We employed naloxone benzoylhydrazone, a kappa3 agonist, and kappa1, mu, and delta antagonist, to better characterize the interaction of cannabinoids with kappa receptors. Naloxone benzoylhydrazone blocked the antinociceptive effects of both intrathecally and intracerebroventricularly administered cannabinoids. Because the cannabinoids are not blocked by mu and delta antagonists, the effects of naloxone benzoylhydrazone are presumed to occur through interaction with kappa receptors. Because the data indicate that naloxone benzoylhydrazone does not block kappa3 receptors, the data indicate that the cannabinoids may interact with kappa1 receptors in the production of antinociception. However, differences in the profile of activity of naloxone benzoylhydrazone and the cannabinoids at kappa receptors exist. Thus, the exact nature of the interaction of the cannabinoids and the kappa receptors to be elucidated.
Analgesics↗
Modulation of free intracellular calcium and cAMP by morphine and cannabinoids, alone and in combination in mouse brain and spinal cord synaptosomes.
Changes in [Ca++]i and cAMP were evaluated as possible mechanisms by which the cannabinoids enhance the antinociception of morphine. The addition of subactive concentrations of delta 9-(THC) and morphine in combination to brain synaptosomes did not result in an enhanced decrease in [Ca++]i; however, this drug combination enhanced decreases in [Ca++]i in spinal cord synaptosomes. The combination of CP55,940 and morphine produced enhanced decreases in [Ca++]i in both brain and spinal cord synaptosomes. In brain synaptosomes, the combination of delta 9-THC and morphine produced an additive decrease in cAMP accumulation, whereas no significant change was observed with this combination in the spinal cord. Thus, the difference in the modulation of [Ca++]i but not cAMP in the brain in vitro may be a predictor of the greater-than-additive antinociceptive effects observe in vivo.
Animals↗
Changes in rat brain cannabinoid binding sites after acute or chronic exposure to their endogenous agonist, anandamide, or to delta 9-tetrahydrocannabinol.
A brain constituent, the N-amide derivative of arachidonic acid, termed anandamide, has been recently proposed as a possible endogenous ligand for the cannabinoid receptor. The present study has been designed to examine whether the acute or chronic exposure to anandamide affected the binding of cannabinoid receptors in specific brain areas as occurred with the exogenous cannabinoid agonist, delta 9-tetrahydrocannabinol (THC). To this end, we measured the maximum binding capacity (Bmax) and the affinity (Kd) of cannabinoid receptors, by using [3H]CP-55,940 binding assays, in membranes obtained from several brain areas of male rats acutely or chronically treated with anandamide or THC. Results were as follows. The acute administration of either anandamide or THC increased the Bmax of cannabinoid receptors in the cerebellum and, particularly, in the hippocampus. This effect was also observed after 5 days of a daily exposure to either anandamide or THC. However, whereas the increase in the Bmax after the acute treatment seems to be caused by changes in the receptor affinity (high Kd), the increase after the chronic exposure may be attributed to an increase in the density of receptors. On the contrary, the [3H]CP-55,940 binding to cannabinoid receptors in the striatum, the limbic forebrain, the mesencephalon, and the medial basal hypothalamus was not altered after the acute exposure to anandamide or THC. However, the chronic exposure to THC significantly decreased the Bmax of these receptors in the striatum and nonsignificantly in the mesencephalon. This effect was not elicited after the chronic exposure to anandamide and was not accompanied by changes in the Kd.(ABSTRACT TRUNCATED AT 250 WORDS)
Analgesics↗
Aversive effects of the synthetic cannabinoid CP 55,940 in rats.
A series of experiments investigated the behavioral and hedonic effects of the synthetic cannabinoid CP 55,940 in male Wistar rats. CP 55,940 had a biphasic effect on locomotor activity, with a 10 micrograms/kg dose causing locomotor stimulation and a 100 micrograms/kg dose causing profound hypoactivity. CP 55,940 (100 micrograms/kg) also caused a marked hypothermia for at least 3 h following administration, while lower doses (2.5 and 10 micrograms/kg) had no effect. CP 55,940 (100 micrograms/kg) had anorexic and hyperdipsic effects for up to 24 h following administration and caused significant reductions in body weight. CP 55,940 (100 micrograms/kg) also caused significant avoidance to a flavoured fluid (saccharin) with which it was paired. In the conditioned place preference paradigm both the 10 micrograms/kg and 100 micrograms/kg doses of CP 55,940 produced significant place avoidance. It is concluded that CP 55,940 is aversive to rats. The possible mechanisms underlying this aversion are discussed.
Analgesics↗
Synthesis and polymerization of new expanding dental monomers.
The objective of this work was to develop polymeric materials that expand slightly upon polymerization and that could potentially be used as matrix resins for dental composites. A series of stereoisomeric alicyclic spiroorthocarbonates (SOC's) that expand when polymerized were synthesized. Three of these SOC racemates were analyzed: cis/cis-, cis/trans- and trans/trans-2,3,8,9-di(tetramethylene)-1,5,7,11-tetraoxaspiro[5.5] undecane. The degrees of expansion, approximately 3.9% and 3.5%, for the cis/cis and trans/trans, were determined by measuring the specific volume of the monomers and polymers in dilute solutions. This method of determining densities and subsequent calculated expansion or shrinkage was validated by duplicating the reported shrinkage of 4-tert-butylphenyl glycidyl ether, styrene, and methyl methacrylate. Based on these data and spectral data obtained using other analytical techniques, these stereoisomeric alicyclic SOC's appear to have potential as nonshrinking polymer or copolymer matrices for dental composites.
Chromatography, Gas↗
Bovine inositol monophosphatase: development of a continuous fluorescence assay of enzyme activity.
This paper describes a continuous assay for the enzyme inositol monophosphatase which has been developed using a new substrate, the fluorescent compound 4-methylumbelliferyl phosphate. The hydrolysis of the phosphate group from this compound can be readily detected by a resultant large red shift in the emission spectrum from 390-450 nm. The kinetic constants for the enzyme using this new substrate are described.
Animals↗
Differences in glucagon-like peptide-1 and GIP responses following sucrose ingestion.
To investigate the mechanism of oral carbohydrate-stimulated secretion of the two most potent incretin candidates, gastric inhibitory polypeptide (GIP) and truncated glucagon-like peptide-1 (tGLP-1), we studied the changes in the plasma levels of these peptides in five healthy men after sucrose ingestion with or without pretreatment with an alpha-D-glucosidase inhibitor (AO-128). After sucrose ingestion, plasma levels of GIP peaked at 15 min and remained high up to 120 min. Plasma levels of GLP-1 NT measured with antiserum R1043 (N-terminal specific) tended to decrease gradually and those of GLP-1 CT measured with antiserum R2337 (C-terminal specific) increased. Therefore, estimated plasma levels of tGLP-1 increased markedly within 30 min, then declined slightly over the next 60 min. After treatment with AO-128 (0.6 mg/day) for 1 week, increases in plasma glucose and insulin levels were attenuated and the increase in plasma GIP levels was diminished, while the increase in tGLP-1 levels was sustained much longer. It is concluded that GIP secretion is stimulated by glucose absorption and tGLP-1 secretion by the presence of sucrose in the gut.
Adult↗
An alpha-glucosidase inhibitor, AO-128, retards carbohydrate absorption in rats and humans.
The present study was designed to determine the possible significance of a therapeutic dose (0.2 mg) of AO-128 on carbohydrate absorption by measuring the breath hydrogen concentration, which is an index of the amount of unabsorbed carbohydrate in the large intestine. Post-prandial hyperglycemia is common among diabetic patients. AO-128, a potent alpha-glucosidase inhibitor, suppressed post-prandial hyperglycemia and hyperinsulinemia in healthy volunteers at a dose of 0.2 mg with each meal. These volunteers increased the breath hydrogen concentration in response to ingestion of non-absorbable lactulose, but decreased only slightly its concentration from the basal level after sucrose ingestion, indicating complete absorption. When AO-128 (0.2 mg) was given with sucrose, hydrogen production increased only slightly compared with placebo, suggesting that the inhibitory effect of AO-128 on sucrose absorption was minimal. Only 5 g of the 100 g of sucrose was not absorbed and this 5% reduction is too small to explain the observed inhibitory effect on the post-prandial rise in plasma glucose. Sucrose loading in rats (about 443 mg) sharply increased blood glucose and was accompanied by the rapid disappearance of sucrose from the upper small intestine. AO-128 (0.03 or 0.1 mg/kg) lessened the elevation of blood glucose after sucrose ingestion. The lower dose (0.03 mg/kg) retarded small intestinal absorption, but did not induce an influx of sucrose into the cecum and large intestine, while the higher dose (0.1 mg/kg) caused an increased influx of sucrose into the large bowel. These results indicated that AO-128 retards the absorption of carbohydrate and reduces post-prandial hyperglycemia.
Adolescent↗