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Biomedical subjects

C B Smith

Publications and source records attributed to C B Smith.

At least 127 records · Page 7Linked to original sources
PubMed1986

Probes for narcotic receptor mediated phenomena. 13. Potential irreversible narcotic antagonist-based ligands derived from 6,14-endo-ethenotetrahydronororipavine with 7-(methoxyfumaroyl)amino, (bromoacetyl)amino, or isothiocyanate electrophiles: chemistry, biochemistry, and pharmacology.

N-Allyl-, N-(cyclopropylmethyl)-, and N-propyl-endo-ethenotetrahydronororipavines (N-substituted 6,14-endo-etheno-4,5-epoxy-3-hydroxy-6-methoxymorphinans) were synthesized with potential acylating or alkylating moieties at the C-7 position (isothiocyanato, (bromoacetyl)amino, and (methoxyfumaroyl)amino) and examined in vivo for their narcotic agonist and antagonist activities and for their ability to interact with opioid receptors in vitro. The N-(cyclopropylmethyl)-substituted compounds were found to have the highest affinity for opioid receptors among these N-substituted compounds, although all of them were found to be reasonably potent narcotic antagonists in the mouse tail flick vs. morphine assay. Their in vivo potency ranged from 1/8 to 4 times that of nalorphine on intravenous injection in mice. Rat brain membrane binding studies indicated that the compounds interacted with opioid receptors with potencies that ranged from 0.5 times that of morphine (8c, 9c, and 10c) to 0.017 that of morphine (8b). Among the compounds studied here, only the previously reported isothiocyanato compound (10c) and (methoxyfumaroyl)amino compound (8c) interacted irreversibly and selectively with mu or delta opioid receptors, respectively, in assays using NG108-15 neuroblastoma-glioma hybrid cells and/or in a rat brain membrane preparation. Both 8c and 10c were found to interact irreversibly, to a limited extent, with kappa opioid sites in rat brain membranes in which the mu and delta opioid receptors were depleted by interaction with the mu-selective irreversible ligand BIT and the delta-selective irreversible ligand FIT. Neither compound showed irreversible actions in the electrically stimulated mouse vas deferens preparation.

Animals↗
PubMed1986

Decreased alpha 2-adrenergic receptors on platelet membranes from diabetic patients with autonomic neuropathy and orthostatic hypotension.

Platelet adrenergic receptors were studied in normal subjects and diabetic patients with autonomic neuropathy to determine the relationship between adrenoreceptor status and orthostatic hypotension. The binding of [3H]clonidine and [3H]yohimbine to platelet membranes was measured in diabetic patients with autonomic neuropathy and orthostatic hypotension (n = 12) and without orthostatic hypotension (n = 11), diabetic patients without autonomic neuropathy (n = 12), and normal subjects (n = 9). Mean basal and standing plasma norepinephrine levels were not different in the four groups, and there was no relationship between orthostasis and norepinephrine responses. The diabetic patients with orthostatic hypotension had a significantly greater fall in mean blood pressure [31 +/- 2.8 (+/- SE) mm Hg] than any of the other three groups. Diabetic patients with diabetic autonomic neuropathy and orthostatic hypotension had a 30-40% decrease in number of platelet alpha 2-adrenergic receptors, as demonstrated by [3H]clonidine and [3H]yohimbine binding. The maximum number of binding sites for clonidine was 34 +/- 2.8 (+/- SE) fmol/mg protein in normal subjects, 27.4 +/- 3.4 in diabetic patients with neuropathy, 26 +/- 2.5 in diabetic patients with autonomic neuropathy without orthostatic hypotension, and 20.4 +/- 3.8 fmol/mg protein in diabetic patients with autonomic neuropathy with orthostatic hypotension (P less than 0.001). The maximum number of binding sites for yohimbine was 112 +/- 12.6 in normal subjects, 127 +/- 10 in diabetic patients without orthostatic hypotension, and 87 +/- 12.4 fmol/mg protein in patients with diabetic autonomic neuropathy with orthostatic hypotension (P less than 0.001). Reduced platelet alpha 2-receptors are associated with postural hypotension in diabetic autonomic neuropathy. If applicable to the postjunctional alpha 2-adrenergic receptor on sympathetic neurons, reduced vascular responses to changes in posture would be expected despite normal or enhanced norepinephrine secretion.

Adult↗
PubMed1986

Dihydromorphine-peptide hybrids have mu receptor antagonistic and delta receptor agonistic activity on the mouse vas deferens and bind with high affinity to opioid receptors in rat brain.

The actions of three morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated, electrically stimulated mouse vas deferens preparation and upon displacement of specifically bound 3H-etorphine in rat brain membranes. NIH-9834 (N-[6, 14-endoetheno-7, 8-dihydromorphine-7-alpha-carbonyl]-L-phenylalanyl-L-leucinol) and its ethyl ester, NIH-9833, were potent agonists upon the vas deferens. ICI-174864, 100 nM, markedly antagonized the actions of both NIH-9833 and NIH-9834 which indicates that these are delta receptor agonists. NIH-9835 (N-[6, 14-endoetheno-7, 8-dihydromorphine-7-alpha-carbonyl]-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl) differs from NIH-9833 and NIH-9834 by the presence of a single amino acid residue. Although this drug had no agonistic activity on the vas deferens, it was a potent antagonist of mu agonists. All three hybrids were potent displacers of 3H-etorphine in rat cerebral membranes. The observation that addition of a single glycyl residue changes dihydromorphine-peptide analogs from potent delta receptor agonists to equally potent mu receptor antagonists suggests that the two receptor sites might be structurally quite similar.

Animals↗
PubMed1986

Presynaptic alpha 2 adrenoreceptor function in dependent rats before and after morphine withdrawal.

Changes in the number of alpha 2 adrenoreceptors in the hippocampus, as measured by the specific binding of 3H-clonidine, were compared to changes in presynaptic alpha 2 adrenoreceptor function in electrically stimulated hippocampal slices. In dependent rats the specific binding of 3H-clonidine was reduced significantly. At 32 h after withdrawal binding began to return toward normal values, and at 72 h after withdrawal was significantly greater than that seen in saline-treated rats. In hippocampal slice experiments sensitivity to clonidine was significantly decreased in morphine-dependent animals and returned toward normal values after withdrawal. At 72 h after withdrawal, the sensitivity to clonidine of the presynaptic alpha 2 adrenoreceptor remained depressed although receptor density as measured in the binding studies was increased. This study suggests that the changes in the function of presynaptic alpha 2 adrenoreceptors might be important in the development of dependence upon morphine.

Animals↗
PubMed1986

Reduction in the incidence of thrombosis by the thromboxane synthetase inhibitor CGS 13080 in a canine model of coronary artery injury.

The antithrombotic potential of the thromboxane (TX) synthetase inhibitor CGS 13080 (CGS) was studied in an anesthetized open-chest canine model of coronary artery intimal wall injury induced by the local application of a low amperage electrical current (100 microA for 6 hr). CGS was administered by i.v. infusion (1 mg/kg/min) beginning 30 min before applying the direct current to the intimal wall of the vessel. CGS did not alter basal values for heart rate, blood pressure or coronary blood flow. After 6 hr of current application to the vessel, 1 of 10 CGS-treated dogs exhibited complete thrombotic occlusion of the circumflex coronary artery compared to 8 of 10 nontreated control dogs (P less than .01). Thrombus masses within the injured left circumflex coronary artery were: Control, 25.9 +/- 4.5 mg (n = 10) and CGS, 11.0 +/- 2.8 mg (n = 10); P less than .01. The concentration of TXB2 determined ex vivo in serum from thrombin-activated whole blood was decreased by CGS administration: Control, 43.15 +/- 16.08 ng/ml (n = 9) vs. CGS, 1.72 +/- .69 ng/ml (n = 10); P less than .001. Ex vivo platelet aggregometry demonstrated that arachidonic acid (0.65 mM)-induced aggregation was reduced from a control value of 82.3 +/- 7.8% (n = 10) to 45.0 +/- 11.3% (n = 10) (P less than .05), whereas aggregation in response to ADP (5 micrograms/ml) or collagen (156 and 312 micrograms/ml) was unaffected. CGS was compared with two other TX synthetase inhibitors, U63557A and OKY1581, for the ability to divert cyclic endoperoxide metabolism to the synthesis of prostaglandin (PG) E2 and prostacyclin in response to stimulation of whole blood in vitro with collagen (25 micrograms/ml). CGS, U63557A and OKY 1581 were found to be equally effective with respect to PGE2 and 6-keto PGF1 alpha production in vitro. The data demonstrate that CGS is an effective antithrombotic agent in vivo and that it selectively inhibits arachidonic acid-induced platelet aggregation ex vivo and the formation of TXA2 in thrombin-activated whole blood.

Animals↗
PubMed1985

Platelet alpha-2-adrenergic dysfunction in negative symptom schizophrenia: a preliminary study.

The specific binding to platelet membranes (Bmax) of 3H-clonidine, an alpha-2 agonist, and 3H-yohimbine, an alpha-2 antagonist, was measured in nine drug-free male schizophrenic patients and repeated after 2 weeks of chlorpromazine (CPZ) treatment. Patients with a lower pretreatment Bmax for 3H-clonidine showed a significantly smaller change in Bmax after treatment, less improvement in their clinical state, as indicated by the change in the Global Assessment Scale (GAS), and a lower posttreatment GAS. Also, they had a significantly higher score for negative symptoms on the Affect Rating Scale both before and after treatment. These findings suggest that schizophrenic patients with relatively subsensitive platelet alpha-2-adrenergic receptors, as measured by 3H-clonidine binding, tend to have more negative symptoms and a diminished alpha receptor binding response and diminished clinical response to CPZ. There were no clinical correlations to 3H-yohimbine binding.

Blood Platelets↗
PubMed1985

Effects of ageing on local rates of cerebral protein synthesis in Sprague-Dawley rats.

The effects of ageing on local rates of protein synthesis in 39 brain structures in resting conscious rats have been examined. Young adult rats (aged 6 months) have been compared with a group of middle-aged/aged rats (aged 15-23 months). The results show that ageing is associated with significant decreases in rates of protein synthesis in the brain as a whole as well as in several specific brain regions. Brain regions involved in visual and auditory function were selectively affected, perhaps due to a chronic lack of sensory input. Several regions involved in motor function and two areas in the limbic system had significantly decreased rates of protein synthesis in the old rats. Notably, there was a significant age-related decrease in protein synthesis in the locus coeruleus which contains the cell bodies of origin of the major ascending noradrenergic innervation of the cortex.

Aging↗
PubMed1985

Effect of clonidine on platelet alpha 2-adrenoreceptors and plasma norepinephrine of children with Tourette syndrome.

Clonidine, an alpha 2-adrenoreceptor agonist, is useful for treating some patients with Tourette syndrome, and it has been suggested that their noradrenergic receptors are 'subsensitive'. The authors measured plasma norepinephrine and specific binding of 3H-clonidine and 3H-yohimbine, an alpha 2-adrenoreceptor antagonist, to receptors on platelet membranes from children with Tourette syndrome. Before clonidine treatment, plasma norepinephrine, the maximum number of binding sites and the dissociation constants for both ligands were the same as for the controls. After two weeks of treatment there was little clinical improvement, but the number of binding sites for 3H-yohimbine decreased and plasma norepinephrine also decreased in four of the five patients. Over the next six months all five patients continued to improve clinically, but both indices of noradrenergic activity returned towards baseline values. The data suggest that clonidine's action may be independent of its prominent effects on alpha 2-adrenergic receptors and norepinephrine release.

Blood Platelets↗
PubMed1985

Pharmacological actions of the racemic and the enantiomeric 1,4-dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benz azo nines (C-homobenzomorphans).

The racemate and optical isomers of the C-homobenzomorphans, 1,4-dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzaz onine, were evaluated in a number of assays sensitive to narcotics of different types. All three C-homobenzomorphans were active in vitro in guinea pig ileum, mouse vas deferens, and rat brain membrane binding assays, but were of low potency. These C-homobenzomorphans showed different profiles of in vivo activity. The (+)-isomer and racemate were active as agonists in the tail-flick assay, whereas the (-)-isomer was inactive. At higher doses, the (-)-isomer and the racemate behaved as antagonists of morphine in the tail-flick assay. All three compounds were active in the phenylquinone test, but naloxone did not block this effect. In addition, all three were potent in the hot-plate test. Neither of the isomers substituted for morphine in dependent rats or monkeys. However, the (+)-isomer precipitated withdrawal in these monkeys. The (-)-isomer produced opioid-like physical dependence in both rats and monkeys. Some of the implications regarding the results with these remarkable homobenzomorphans are discussed.

Analgesics↗
PubMed1984

Platelet alpha 2-adrenergic receptor binding and plasma catecholamines. Before and during imipramine treatment in patients with panic anxiety.

Specific binding of tritiated clonidine, an alpha 2-adrenergic receptor agonist, and tritiated yohimbine, an alpha 2-adrenergic receptor antagonist, to platelet membranes was measured in persons with panic attacks or major depression and in normal subjects. Plasma catecholamine levels were measured in patients with panic attacks and in normal subjects. The number of binding sites in patients with panic attacks, as measured with tritiated clonidine, was lower than in depressed persons and was the same as in normal subjects. The number in patients with panic attacks, as measured with tritiated yohimbine, was lower than in either depressives or normal subjects. Catecholamine levels were somewhat higher in patients with panic attacks than in normal subjects. Treatment with imipramine hydrochloride decreased the number of sites, as measured with either ligand, in both patient groups and increased catecholamine levels in patients with panic attacks.

Adolescent↗
PubMed1984

Altered platelet alpha 2 adrenoreceptors in orthostatic hypotension.

Alpha 2 adrenergic agonists have been used to raise blood pressure in patients with idiopathic orthostatic hypotension (IOH). In an attempt to define the mechanism of action of these agents, radioligand binding of [3H]clonidine, an alpha 2 agonist, and of [3H]yohimbine, an alpha 2 antagonist, to human platelet membranes from a patient with IOH was performed to determine the maximum number (Bmax) and dissociation constant (KD) for this receptor. There was a marked decrease in receptor number in this patient when compared to normal subjects. In normal volunteers the specific binding of [3H]clonidine yielded a mean Bmax of 33 +/- 2 fmol/mg protein and a KD of 5.5 +/- 0.6 nM, while for the patient the Bmax was 20 fmol/mg protein and the KD was 7.4 nM. For [3H]yohimbine binding in normals, the Bmax was 165 +/- 12 fmol/mg protein and the KD was 4.0 +/- 0.5 nM, whereas for the patient the Bmax was 65 fmol/mg protein and the KD was 12.0 nM. Alpha 2 adrenergic agonists such as clonidine decrease blood pressure by stimulating central presynaptic alpha 2 sites, and thus inhibiting sympathetic activity. There are also alpha 2 adrenergic receptor sites postsynaptically on vascular smooth muscle. The presence of this receptor postsynaptically in a patient with a reduction of the presynaptic inhibitory sites could account for clonidine's pressor activity in patients with IOH. Further study of both alpha 2-adrenergic receptors in patients with IOH may be important in developing an understanding of central and peripheral mechanisms in the control of blood pressure.

Adult↗
PubMed1984

Changes occur in central adrenoreceptor function following long-term morphine treatment and during morphine withdrawal.

Radioligand binding techniques were used in combination with in vivo electrophysiological recording to characterize changes in beta adrenoreceptor activity in various brain areas in rats treated chronically with morphine. Following chronic morphine treatment, the maximum number of specific binding sites for 3H-dihydroalprenolol (3H-DHA) in parietal cortex and hippocampus showed a biphasic change, indicating an initial increase and decrease (relative to controls) in beta adrenoreceptors in these regions with time during withdrawal. No appreciable changes were observed in the dissociation constants for 3H-DHA binding. The changes in cortical beta adrenoreceptor density found in early (8 hr) and later phases (32 hr) of withdrawal were paralleled by a selective increase and decrease, respectively, in cortical neuron sensitivity to noradrenergic stimulation. These results suggest a possible linkage between changes in central adrenoreceptor function and the formation and/or expression of opiate dependence.

Adrenergic beta-Agonists↗
PubMed1984

Comparison of "selective" opiate receptor antagonists on the isolated mouse vas deferens.

The selectivity and relative potencies of opiate receptor antagonists were compared on the mouse vas deferens preparation. ICI-174864 was found to be a highly selective antagonist at delta opiate receptors equal in potency to naltrexone in blocking the actions of delta agonists. Although less potent than naltrexone, beta-funaltrexamine (beta-FNA) and Mr-1452, like naltrexone, were less selective in that they blocked the actions of mu, delta and kappa agonists. The relative potencies of beta-FNA and Mr-1452 in antagonizing the three types of agonists also were similar to naltrexone.

Animals↗
PubMed1984

Platelet alpha 2-adrenergic receptors in schizophrenic patients before and after phenothiazine treatment.

The specific binding to isolated platelet membranes of 3H-clonidine, an alpha 2-adrenergic receptor partial agonist, and 3H-yohimbine, an alpha 2-adrenergic receptor antagonist, was measured in male, drug-free schizophrenic patients. The maximum number of binding sites (Bmax) for 3H-yohimbine was significantly lower in these patients than in normal subjects. Treatment with chlorpromazine (CPZ) for 2 weeks further decreased the Bmax for both ligands. Plasma catecholamine levels were determined before and after treatment. Before treatment, levels of dopamine and norepinephrine (NE) were within a normal range, while epinephrine (E) levels were significantly elevated. CPZ treatment significantly increased plasma NE levels, but decreased E levels to a normal range. These observations suggest that schizophrenia might be associated with abnormal noradrenergic function that is reflected by a decreased number of platelet alpha 2-adrenergic receptors.

Adult↗