Biomedical subjects
M Williams
Publications and source records attributed to M Williams.
Antihypertensive beta-adrenergic blocking agents: N-aralkyl analogues of 2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine.
An interest in dual-acting antihypertensive agents, specifically those related to (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1), led us to probe the contribution of the side-chain amino substituent in this series. The ability of 1 and its various analogues to displace radiolabeled alpha 1 (WB-4101 and prazosin) and beta (dihydroalprenolol) adrenergic receptor ligands was assessed by receptor-binding techniques. Most of the compounds exhibited high beta-adrenoceptor binding affinities, but only the N-aralkylamino-substituted compounds showed high alpha 1-adrenoceptor affinities. Therefore, the vasodilation shown by 1 was not due to an interaction with the alpha 1 adrenoceptor. The aralkylamino analogues of 1 in spontaneously hypertensive rats and anesthetized dogs exhibited antihypertensive activity and alpha 1-adrenoceptor blocking properties. Unlike the preference shown by beta-adrenoceptors for S enantiomers in this oxymethylene class of beta blockers, the chirality at the secondary hydroxy center made only a minor contribution to the affinity for the alpha 1-adrenoceptor and even less of a contribution to the observed antihypertensive effects. This lack of chiral influence at the hydroxy center confirmed what had been previously observed in more limited studies with the isomers of both labetalol and medroxalol.
Synthesis and receptor binding studies relevant to the neuroleptic activities of some 1-methyl-4-piperidylidene-9-substituted-pyrrolo[2,1-b][3]benzazepine derivatives.
The synthesis of a series of 1-methyl-4-(9-substituted-11H-pyrrolo[2,1-b]benzazepin-11-ylidene)piperidines (4a-f) and 1-methyl-4-(9-substituted-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidines (4g-l) is described. As with th e 3-substituted cyproheptadine compounds 1b-e, atropisomerism exists in 4b-f, but unlike the enantiomers of 1b-e, the pyrrolobenzazepine enantiomers racemize at room temperature. Thus, the bromo compound (+)-4b has a half-life of 128 +/- 1 min at 25 degrees C, while the chloro compound (-)-4c has a half-life of 114 +/- 9 min at 25 degrees C. Compounds 4a-l have been examined for receptor binding affinities in assays that have been recognized as predictive for antipsychotic activity. The displacement of specifically bound tritiated ligands, comprising the dopamine antagonist [3H]spiperone, the dopamine agonist [3H]apomorphine, the muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate (QNB), the alpha-adrenergic antagonist [3H]prazosin, the alpha-adrenergic agonist [3H]clonidine, the serotonin-1 binding agent [3H]serotonin, and the mixed serotonin agonist-antagonist [3H]lysergic acid diethylamide (LSD), by 4a-l has been measured utilizing membrane preparations of mammalian brain. Certain of the features of the receptor binding of these compounds have been shown to be common to several of the receptor sites. Data from these binding studies have been compared to corresponding data previously obtained for a series of chiral 3-substituted cyproheptadine analogues, and the receptor binding data of the two classes of compounds are discussed with respect to their molecular geometries.
The effect of dexamethasone on the radiation sensitivity of cultured cells.
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Organizational climate: a measure of faculty and nurse administrator perception.
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RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane): central effects of a new dopamine receptor agonist.
Apomorphine (APO), 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127) and 2-di-n-propylamino-5,8-dimethoxytetralin (JMC-181) were examined on a variety of biochemical and pharmacological assays to determine their possible interaction with dopamine (DA) receptors. Nanomolar concentrations of all three compounds displaced [3H]APO from specific high-affinity binding sites in rat striatal membrane preparations, while higher concentrations were required to displace [3H]spiperone or [3H]rauwolscine. APO caused a concentration-dependent increase in the ability to stimulate postsynaptic DA receptors associated with adenylate cyclase (D1-sites) in the carp retina, whereas RDS-127 or JMC-181 were inactive in concentrations up to 300 microM. APO was very active in causing contralateral turning behavior in rats with a 6-hydroxydopamine lesioned substantia nigra (SN); RDS-127 was approximately 8 times less potent in producing contralateral rotations and JMC-181 was inactive. RDS-127 produced biphasic, dose-related changes in rat spontaneous locomotor activity similar to that reported for APO. The locomotor stimulant effects of RDS-127 were 3 times more potent and 4 times greater in duration than that induced by APO. JMC-181 produced primarily sedation in the doses tested. APO, RDS-127 and JMC-181 were active in inhibiting the accumulation of dopa in the caudate nucleus and olfactory tubercle using the in vivo gamma-butyrolactone procedure; 5-hydroxytryptophan accumulations were not altered significantly. RDS-127 was 7 times more potent than APO in inhibiting dopa accumulation in the caudate nucleus and equipotent to APO in the olfactory tubercle. Dopa accumulation was weakly inhibited by JMC-181. When single unit extracellular action potentials were recorded from purported DA-containing neurons in the SN, RDS-127 decreased the firing of neurons in the pars compacta of SN (ID100 = 40 +/- 10 nmol/kg i.v.). In contrast, firing of units in the pars reticulata of SN were not altered or increased in response to RDS-127. The biochemical electrophysiological and behavioral effects of RDS-127 were blocked or reversed by DA receptor antagonists. These data indicate that RDS-127 is significantly more selective than APO in preferentially activating DA autoreceptors as opposed to the postsynaptic DA receptors in the nigrostriatal pathway. The possibilities of designing potent, long acting, nonergot, noncatechol-containing DA receptor agonists are discussed.
Planning operating departments No. 7. Commissioning theatres.
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Minor gynaecology of the climacteric.
The climacteric is a transitional phase of one to five years during which the genital organs involute in response to the cessation of gonadal activity. During the climacteric women suffer a range of gynaecological disorders. The patient's worries discussed in this article are particularly pertinent to general practice.
Antiparasitic efficacy of ivermectin in naturally parasitized sheep.
Sixteen sheep harboring naturally acquired parasitisms were allocated to 1 of 2 treatment groups: (i) sheep given ivermectin in an oral solution at the dosage rate of 200 micrograms/kg of body weight, and (ii) those given the vehicle at a dosage rate of 0.25 ml/kg. All animals were necropsied at 2 weeks after treatment. Parasites and percentages of parasitic reductions, as demonstrated in this trial, were: Dictyocaulus filaria (99.4%), Oestrus ovis first stage instars (100%), Trichuris ovis (98.9%), Strongyloides papillosus (99.8%), Nematodirus spathiger (100%), arrested 4th stage Nematodirus spp (96.2%), Trichostrongylus colubriformis (100%), T axei (100%), Oster tagia circumcincta (100%), Haemonchus contortus (100%), and arrested Haemonchus spp 4th stage larvae (99.9%). The sheep showed no adverse effects due to ivermectin or vehicle administration.
Interaction of the putative dopamine autoreceptor agonists 3-PPP and TL-99 with [3H]apomorphine binding sites in rat striatal membranes.
Examination of the binding of [3H]apomorphine to rat striatal membranes in the presence and absence of the dopamine antagonist, domperidone, confirmed the previously reported presence of two classes of dopamine binding site, those designated D2 which show a high affinity for both agonist and antagonists and those designated D3 which have a high affinity for agonists and a low affinity for antagonists. In contrast to the previously reported single high affinity (KD congruent to 1 nM) D2- and D3-binding sites, two lower affinity sites (D2KD = 7-50 nM; D3KD = 41 nM) were also observed. Examination of the binding characteristics of the putative dopamine autoreceptor agonists, 3-PPP (N,N-propyl-3-(3-hydroxyphenyl)piperdine) and TL-99 (6,7-dihydroxy-2-dimethylaminotetraline) showed that they, like a number of other dopamine agonists including n-propylnorapomorphine, apomorphine and dopamine showed no preferential affinity for the D3, presynaptic binding site. It is concluded that the selectivity of dopamine agonists for the autoreceptor cannot be assessed by the in vitro radioligand binding parameters defined by the use of domperidone.
Interaction of 2-phenylaminoadenosine (CV 1808) with adenosine systems in rat tissues.
2-Chloroadenosine (2-CADO) and 2-phenylaminoadenosine (CV 1808) were compared in a CNS purinergic receptor binding assay and the inhibition of neurogenic contractions of the vas deferens. Both 2-CADO and CV 1808 are more potent than adenosine in both preparations. CV 1808 was 10 times more active than dipyridamole in enhancing the response of the vas deferens to exogenous adenosine. Thus, CV 1808 may owe its potent coronary vasodilator activity to both a direct action on adenosine receptors and the ability to augment adenosine responses.
Inhibition of postsynaptic dopamine-sensitive adenylate cyclase in carp retina by the putative dopamine autoreceptor agonist, 3-PPP.
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Practice nurses: accountability writ large.
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Potent dopamine agonist activity of a novel ergoline, 6-ethyl-9-oxaergoline (EOE).
6-Ethyl-9-oxaergoline (EOE) and its enantiomers were compared with apomorphine in a number of tests designed to measure dopamine (DA) agonist activity within the central nervous system. In rats, the tests were: interaction with DA receptors labeled with 3H-apomorphine or 3H-spiroperidol; the effects on DA synthesis as assessed by the gamma-butyrolactone procedure; turning in 6-OHDA lesioned animals; stereotypy; and, slowing of DA cell firing rates. In the mouse, locomotor activity, hypothermia and postural asymmetry in caudectomized animals were studied. Emesis in the beagle was also examined. The (-)-enantiomer of EOE was more potent than either the (+)-enantiomer or the racemate in all tests. With the exception of inducing stereotypy and the displacement of 3H-apomorphine from rat striatal membranes, (-)-EOE was equi- or more potent than apomorphine in all test procedures. (-)-EOE was effective following oral administration and exhibited a longer duration of action than apomorphine. The results indicate EOE is a potent DA agonist.
Fatal Haemophilus influenzae type f infection.
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Interaction of avermectins with [3H]beta-carboline-3-carboxylate ethyl ester and [3H]diazepam binding sites in rat brain cortical membranes.
The binding of [3H] beta-carboline-3-carboxylate ethyl ester ([3H] beta-CCE), a ligand for the benzodiazepine receptor in the mammalian CNS, to rat cortical membranes, is enhanced by avermectin B1a and its therapeutic formulation, Ivermectin. In contrast to the effects of the avermectins on [3H]diazepam binding, which involve changes in both receptor affinity and number, increases in beta-CCE binding, which are much less than those observed for the benzodiazepine ligand, involve only alterations in receptor number. This Bmax increase is bicuculline insensitive whereas Ivermectin effects on benzodiazepine binding are partially antagonized by GABA antagonist. The data suggest a differential interaction by the avermectins on benzodiazepine and beta-CCE binding sites in rat cortical membranes and indicate that these macrolide anthelmintics may be a useful tool for characterizing benzodiazepine/anxiolytic receptor subtypes.
Interaction of the putative dopamine autoreceptor agonists, 3-PPP and TL-99, with the dopamine-sensitive adenylate cyclase of carp retina.
The putative dopamine autoreceptor agonists, 3-PPP and TL-99 were examined for their ability to stimulate postsynaptic dopamine receptors associated with adenylate cyclase (D1-receptors) in the carp retina. In intact pieces of retina, 3-PPP had no significant effect on cyclic AMP production at concentrations up to 100 microM, whereas the aminotetralin, TL-99, caused a concentration-dependent increase in cyclic AMP levels with an approximate EC50 of 3.6 microM. Dopamine and ADTN had EC50 values of 3.5 and 3.1 microM respectively. Furthermore, in homogenates of the retina, 100 microM ADTN and 100 microM TL-99 stimulated adenylate cyclase activity 92 and 79% respectively as compared to the stimulation evoked by 100 microM DA. In contrast, 100 microM 3-PPP was essentially inactive at stimulating adenylate cyclase in carp retinal homogenates. These findings suggest that TL-99 can interact with postsynaptic D1-receptors and is not as selective a dopamine autoreceptor agonist as 3-PPP, which has no apparent activity at the D1-receptor.
Neurotensin effects on brain dopaminergic systems.
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