Cyprodime analogues: synthesis and pharmacological evaluation.
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Animals↗
Biomedical subjects
C F Smith
Publications and source records attributed to C F Smith.
Synthesis and biological evaluation of 14-alkoxymorphinans. 2. (-)-N-(cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one, a selective mu opioid receptor antagonist.
(-)-N-(Cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one (2) was synthesized with 4,14-dimethoxy-N-methylmorphinan-6-one (1) as starting material. In vivo and in vitro experiments show 2 (cyprodime) to be a pure opioid receptor antagonist. Some of these tests (opioid receptor binding assays, guinea pig ileal longitudinal muscle preparation, rat and mouse vas deferens preparation, acetic acid writhing antagonism test) indicate that 2 is a selective mu opioid receptor antagonist.
Animals↗
Heteroaromatic analogues of the alpha 2-adrenoreceptor partial agonist clonidine.
A 1,4-dioxane analogue (1) of the alpha 2-adrenoreceptor partial agonist clonidine (2) has previously been shown to possess an interesting but complex pharmacological profile. In this study, from a series of other heterocyclic analogues of clonidine, the 1,4-oxazines 6 and 12 were found to resemble 1 in that they are partial alpha 2-agonists in the periphery and are excluded from the central nervous system. However, when given directly into the brain, they behave as pure alpha 2-antagonists.
Adrenergic alpha-Agonists↗
The carbon dioxide laser. A potential tool for orthopedic surgery.
Arthroscopic laser surgery was performed in 325 knee joints between January 1985 and August 1988 with no significant lasting complications. The CO2 laser is especially effective in the "tight knee" for high surface area, low volume lesions, and chondromalacia. Arthroscopic laser surgery is also being performed as part of a multicenter study. Although the results are satisfactory to date, the use of the laser on the spine and joints other than the knee and for PMMA removal is experimental.
Ankle Joint↗
Comparing the costs of i.v. drug delivery systems.
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Costs and Cost Analysis↗
Choose i.v. delivery systems wisely, study urges.
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Disposable Equipment↗
Indoline analogues of idazoxan: potent alpha 2-antagonists and alpha 1-agonists.
The synthesis and alpha-adrenergic activity of a series of substituted 2-imidazolinylindolines are described. Substitution in the indoline ring generated compounds with a spectrum of adrenoceptor antagonist/agonist profiles that proved sensitive to both the nature and position of the substituent. Many of the derivatives possess greater presynaptic antagonist potency than the corresponding benzodioxan 1, dihydrobenzofuran 2, and indan 3 analogues; however, this alpha 2-antagonism is often accompanied by alpha 1-agonist activity. It was not possible to separate alpha 2-antagonist from alpha 1-agonist properties in this series. Compounds of most interest proved to be the N-ethyl 6, 5-chloro-N-methyl 18, and 5-chloro-N-ethyl 23 derivatives, all being potent alpha 2-antagonists and alpha 1-agonists. Substitution at the 4- and 7-position of the indoline ring generally gave compounds with nonselective agonist properties.
Adrenergic alpha-Agonists↗
Quantitation of corneal neovascularization using computerized image analysis.
We have developed a method for quantitating corneal neovascularization, induced in anesthetized rats by silver nitrate/potassium nitrate cauterization, using a LeMont OASYS video input image analyzer. Corneal vessels are visualized by perfusing the upper half of deeply anesthetized animals with a mixture of 10% india ink, 11% gelatin in lactated Ringer's solution. The eyes are then rapidly cooled using a stream of compressed dichlorodifluoromethane (Freon) to solidify the gelatin mixture. Magnified images of flat preparations of the corneas are acquired using a television camera attached to a dissecting microscope. The images are electronically converted to digital form and the digitized data are stored in the image analyzer. The area of the cornea and blood vessels are independently determined by analyzing the digitized data as discrete values of varying shades of gray (gray-scale analysis). The area and gray scale of the injury and its distance from the corneoscleral limbus can also be measured to determine variability of location and intensity of the injury in different animals. This technique allows the area occupied by new blood vessels during studies on corneal neovascularization in rats to be rapidly quantitated.
Animals↗
Comparison of seven methods of preparing and administering small-volume injections.
The time and costs associated with preparing and administering small-volume injections using seven infusion systems were compared. Thirteen demographically diverse hospitals were chosen as study sites, all under a common protocol. The systems compared were the CRIS controlled-release infusion, minibag, frozen ready-to-use minibag, drug manufacturer-supplied piggyback, syringe pump, volume-control set, and ADD-Vantage systems. Care was taken to ensure that similar drugs (i.e., drugs with equivalent preparation steps) were studied in the same test systems at the hospitals. The mean preparation time for the CRIS controlled-release infusion system was significantly longer than the times for the frozen ready-to-use minibags and ADD-Vantage system and significantly shorter than the times for the minibag and syringe pump systems. Medication administration time for initial doses was found to be significantly shorter with the CRIS system than with the volume-control and ADD-Vantage systems; the time required to administer subsequent doses of small-volume injections was shorter with CRIS than with all other systems except the ADD-Vantage system. When total material costs plus the cost of labor involved in both pharmacy and nursing were combined, CRIS proved to be the least expensive system to use, primarily because of the time and cost savings associated with its use for administration of subsequent doses. Of the seven admixture systems studied, the CRIS system proved to be the least expensive to use when labor and material costs associated with preparation and administration of six doses of an injectable drug were considered.
Cefazolin↗
16-Me cyprenorphine (RX 8008M): a potent opioid antagonist with some delta selectivity.
16-Me cyprenorphine (RX 8008M) has been investigated in a number of isolated tissue preparations and found to be a pure opioid antagonist with Ke values at the delta, mu and kappa receptors of 0.73, 1.77 and 59.6 nM respectively. Comparisons of the mu, kappa and delta Ke values with a number of other antagonists in the mouse vas deferens have been made and show that the 16-Me substituent results in a marked enhancement of delta activity, making RX 8008M the most selective non-peptide delta antagonist available at the present time.
Animals↗
Effect of methoxy substitution on the adrenergic activity of three structurally related alpha 2-adrenoreceptor antagonists.
We have recently reported the synthesis and alpha 2-antagonist activity of the methoxy derivative 2 [2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline] and described the enhanced potency of this compound over the parent 1,4-benzodioxan, idazoxan, in reversing the inhibition caused by alpha 2-adrenoreceptor agonists of the electrically induced twitch in the rat or mouse vas deferens. It was of interest to us to discover whether a similar substitution in the structurally related alpha 2-adrenoreceptor antagonists piperoxan, prosympal, and fenmetazole would similarly enhance potency. We subsequently discovered that this was not so and potency was decreased markedly. In particular, that of the methoxy derivative of piperoxan was ca. 220 times less than the parent structure.
Adrenergic alpha-Antagonists↗
Alpha-adrenoreceptor reagents. 4. Resolution of some potent selective prejunctional alpha 2-adrenoreceptor antagonists.
The resolution of three 2-substituted derivatives of idazoxan is described. The enantiomers show large separations in activity in a variety of in vitro and in vivo tests, and the active isomers are all potent and selective antagonists at the alpha 2-adrenoreceptor. The significance of these results in relation to those published on the enantiomers of idazoxan and to those on optically active alpha 2-adrenoreceptor agonists is discussed.
Adrenergic alpha-Antagonists↗
Delta receptors in the rat vas deferens.
The effects of the delta-selective antagonist ICI 174864 and naltrexone on the dose-response curves to the mu-selective agonist RX 783006 and D-ala-D-leucine enkephalin (DADL) have been investigated in the rat isolated vas deferens preparation (RVD) set up in Krebs solution containing half the normal Ca++ concentration. The results obtained provide very strong evidence for the existence of both mu- and delta-receptors in this preparation. The Ke values of a number of opioid antagonists v. DADL in the RVD have been determined and compared to the Ke values obtained in the mouse vas deferens assay (MVD). The very good correlation (slope = 1.01, r = 0.98) obtained between the Ke values from the 2 preparations confirms the presence of a delta-receptor in the RVD.
Animals↗
An evaluation of methods to quantitate the chick chorioallantoic membrane assay in angiogenesis.
The vascular responses by chick chorioallantoic membranes (CAM) to more than 150 normal and chemically injured rat corneas grafted to shell-less chicken CAMs were evaluated independently by three observers in a masked fashion by in vivo stereomicroscopy, projections of colored transparencies, and by light microscopy of tissue sections of the grafts. The experience gained from this study is reviewed as a point of focus for the strengths and weaknesses of the CAM technique in the assay of potential angiogenic substances. Despite certain shortcomings, the CAM technique can provide useful information relevant to studies on angiogenesis, particularly when the subjective CAM method is supplemented by histological evaluation of grafted tissues.
Allantois↗
Intercellular relationships in the synthesis of macromolecules by organ cultures of corneas.
Sepharose CL-4B chromatography of guanidine hydrochloride and aqueous extracts of 3H-glucosamine labeled intact corneal tissue reveals four peaks representing proteoglycans and glycoproteins. To evaluate the universality of the 4th peak, hereafter designated as Sepharose CL-4B (IV), its presence was investigated in rabbit, bovine, cat, rhesus monkey, and human corneal preparations. Following incubation in isotopically labeled medium, corneas were extracted with aqueous and/or 4M guanidine hydrochloride and subjected to Sepharose CL-4B chromatography. Sepharose CL-4B (IV) was detected in all species studied; 3H-glucosamine and 14C-amino acids, but not 35SO4, were incorporated into this peak which eluted in the range consistent with an apparent molecular weight of approximately 30,000 D. To determine which layers were involved in the synthesis of Sepharose CL-4B (IV) the layers of the rabbit cornea were incubated separately (stroma scraped of endothelium and/or epithelium, epithelium only, endothelium only). A distinct Sepharose CL-4B (IV) peak was not identified in the chromatographs obtained from organ cultures of corneal epithelium, endothelium, or from corneal stroma scraped of epithelium and/or endothelium. This decrease in Sepharose CL-4B (IV) synthesis occurred even if the scraped cornea was not allowed to expand in volume by compressing it beneath a membrane porous to the incubation medium. Thus, Sepharose CL-4B (IV) synthesis was enhanced significantly by the stroma being in conjunction with other corneal cells as they exist in vivo.
Animals↗
Morphine, but not diacetyl morphine (heroin), possess opiate antagonist activity in the mouse vas deferens.
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Animals↗
Alpha-adrenoreceptor reagents. 2. Effects of modification of the 1,4-benzodioxan ring system on alpha-adrenoreceptor activity.
Modification of the 1,4-benzodioxan ring present in RX 781094 has not previously been considered. This paper describes a number of analogues of this ring system, including compounds in which one of the oxygen atoms has been replaced by a methylene group and also those in which the ring size has been changed to give, for example, furan and thiophene derivatives. The dihydrobenzofuranylimidazoline compound 7 is the only analogue possessing presynaptic antagonist potency potency and selectivity comparable to that of 1. In view of this result, a number of derivatives was prepared to determine the structure-activity relationships within this series. Many derivatives, as well as the parent compound 7, were found to possess presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties. Two of the selective presynaptic antagonists, 13 and 14 possess greater potency and selectivity than that possessed by 1. The 5-chloro derivative 25 is twice as potent as after oral administration but only about half as potent when given intravenously.
Adrenergic alpha-Antagonists↗
The response of growing broiler chickens to dietary contents of protein, energy and added fat.
The results of 47 experiments with broilers over the period 1974 to 1983 were selected for regression analysis. Included were those dealing with the relationship of growth and food utilisation to content of dietary protein (DP), metabolisable energy (DME) and added fat (DAF) in conventional feedingstuffs. Significant correlations were found between DP and DME (0.50; P less than 0.01), DP and DAF (0.61; P less than 0.01), and DME and DAF (0.65; P less than 0.01) contents. Using multiple regression models, growth and food utilisation efficiency (FUE) were found to be dependent on the linear and quadratic effects of DME (r2 values = 0.67 and 0.64 respectively). Growth and FUE were also dependent on the linear and quadratic effects of DP (r2 values = 0.70 and 0.49 respectively). By including the effects of DME, DP and DAF in the gain and FUE models it was shown that growth and FUE were dependent on DME, DP and DAF (r2 values = 0.76 and 0.79 respectively). It was concluded that hypotheses concerning the broiler's response to DME and DAF were both correct but incomplete. DME, DP and DAF contents must all be known to predict accurately growth and FUE.
Animals↗