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Biomedical subjects

S J Peroutka

Publications and source records attributed to S J Peroutka.

At least 145 records · Page 8Linked to original sources
PubMed1986

Canine basilar artery contractions mediated by 5-hydroxytryptamine1A receptors.

A series of 11 agents was analyzed at both 5-hydroxytryptamine1A (5-HT1A) sites labeled by [3H]-8-hydroxy-2-(N,N-dipropylamino)tetralin and total 5-HT1 binding sites labeled by [3H]-5-HT in rat brain membranes. Three distinct patterns of relative inhibition were noted. First, drugs such as 8-hydroxy-2-(N,N-dipropylamino)tetralin n-(3-acetylaminophenyl)piperazine hydrochloride, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-1,2-benziso-thiazol-3 -(2H)one-1,1-dioxidehydrochloride] and buspirone display 1.0 to 15 nM potency for the 5-HT1A subpopulation of 5-HT1 binding sites but are more than two orders of magnitude less potent at total 5-HT1 sites. Secondly, 5-methoxy-N,N-dimethyltryptamine and methysergide are approximately one order of magnitude more potent at 5-HT1A than total 5-HT1 sites. In the third group, 5-HT, d-lysergic acid diethylamide, 1-(m-trifluoromethylphenyl)piperazine, 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyrimidinyl) 1H indole, quipazine and pirenperone are essentially equipotent at both 5-HT1A and 5-HT1 sites. Thus, the 5-HT1A binding site has a pharmacological profile which, depending on the agents studied, could be significantly different from the pharmacological profile derived from total 5-HT1 binding. Drug interactions were also analyzed with canine basilar artery segments using 5-HT, 10 putative serotonergic agonists and a selective 5-HT2 antagonist, pirenperone. The maximal contraction was obtained using 5-HT (Cmax = 6.6 +/- 0.6 g). However, each of the 10 other putative 5-HT agonists elicited a less forceful contraction of the canine basilar artery.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Neurotransmitter receptor binding studies predict antiemetic efficacy and side effects.

Radioligand binding studies were used to analyze the interaction of antiemetics with central dopamine D2 and alpha-adrenergic1 receptors. The affinity of antiemetics for dopamine D2 receptors labeled by 3H-spiperone significantly correlated with clinically effective drug doses (r = 0.92; P less than 0.01). Furthermore, the relative inhibition of alpha-adrenergic1 receptors as measured by 3H-WB 4101 binding predicts the clinical side effects of sedation and orthostatic hypotension. Neurotransmitter receptor binding analysis provides a rapid and sensitive technique for measuring antiemetic potency as well as associated side effects.

Animals↗
PubMed1985

Selective labeling of 5-HT1A and 5-HT1B binding sites in bovine brain.

Drug interactions with serotonin(1A) 5-HT1A and serotonin(1B) (5-HT1B) binding sites were analyzed in bovine brain membranes. 5-HT1A binding sites were directly labeled with [3H]8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in bovine hippocampal membranes. 5-HT1B binding sites were labeled by [3H]5-HT in bovine striatal membranes where less than 15% of specific binding sites are sensitive to nanomolar concentrations of 8-OH-DPAT. Each of the 12 agents tested was more potent at the 5-HT1A than 5-HT1B binding site. 5-HT, bufotenine, N,N-dimethyltryptamine (DMT) and quipazine were only slightly more potent at the 5-HT1A binding site. By contrast, 8-OH-DPAT, TVX Q 7821 and buspirone were significantly more potent at [3H]8-OH-DPAT binding sites in bovine hippocampus than at [3H]5-HT binding sites in bovine striatum. These findings suggest that 5-HT1A, and 5-HT1B binding sites have distinct pharmacological profiles and can be directly labeled with appropriate [3H]ligands in specific brain regions.

Animals↗
PubMed1985

Selective interaction of novel anxiolytics with 5-hydroxytryptamine1A receptors.

Radioligand binding studies were used to analyze the interactions of two novel anxiolytics, buspirone and TVX Q 7821, with a series of 10 neuronal membrane receptor sites. Buspirone (IC50 = 24 nM) and TVX Q 7821 (IC50 = 9.5 nM) display the highest affinity for 5-hydroxytryptamine1A (5-HT1A) binding sites labeled by 3H-8-hydroxy-2-(di-n-pro-pylamino) tetralin (DPAT). By contrast, buspirone is 16-fold weaker at dopamine (D2) receptors (IC50 = 380 nM), whereas TVX Q 7821 is 6-fold less potent at alpha-adrenergic1 sites (IC50 = 58 nM). At the other receptors studied, buspirone and TVX Q 7821 had similar pharmacological profiles. Both agents display moderate affinity for histamine (H1), alpha-adrenergic2, and 5-HT2 binding sites. The drugs are essentially inactive at 5-HT1B, calcium channel antagonist, muscarinic cholinergic, and benzodiazepine receptors. These results suggest that the anxiolytic effects of buspirone and TVX Q 7821 may be mediated by central 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

Central effects of RDS-127: sexual behavior after intracerebroventricular administration and in vitro receptor binding studies.

RDS-127, in a dose-related manner, induced seminal emission ex copula after intracerebroventricular (i.c.v.) administration. In mating tests initiated 6 min after i.c.v. administration, RDS-127 induced decreases in ejaculation latency and intromission frequency, with some rats ejaculating on the initial intromission. Additionally, penile reflexes were eliminated by 150 micrograms and 600 micrograms, but not by an intermediate dose. In in vitro radioligand binding studies, RDS-127 potently displaced [3H]DPAT binding to 5-HT1A sites in rat cortex (Ki = 14 +/- 4 nM) and was only moderately effective in displacing [3H]spiperone binding to dopaminergic D2 sites in rat striatum. RDS-127 was essentially ineffective at 5-HT1B sites labeled by [3H]5-HT in rat striatum (Ki = 13 000 +/- 4 000 nM). These data demonstrate that centrally administered RDS-127 mimics the previously reported alterations in sexual behavior after systemic treatment and that RDS-127 is a high affinity 5-HT1A agent with low affinity at the 5-HT1B binding site.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

Phorbol ester effects on neurotransmission: interaction with neurotransmitters and calcium in smooth muscle.

Stimulation of the phosphatidylinositol cycle by neurotransmitters generates diacylglycerol, an activator of protein kinase C, which may regulate some forms of neurotransmission. Phorbol esters, potent inflammatory and tumor-promoting compounds, also activate protein kinase C. We demonstrate potent and selective effects of phorbol esters on smooth muscle, indicating a role for protein kinase C in neurotransmission. In rat vas deferens and dog basilar artery, phorbol esters synergize with calcium to mimic the contractile effects of neurotransmitters that act through the phosphatidylinositol cycle. In guinea pig ileum and rat uterus, phorbol esters block contractions produced by these neurotransmitters.

Animals↗
PubMed1985

Calcium channel antagonism by pizotifen.

Pizotifen is a clinically effective anti-migraine agent with potent anti-serotonin and anti-histamine properties. Pizotifen is equipotent in blocking contractions of the canine basilar artery induced by serotonin, norepinephrine or calcium chloride. As a result, the primary action of pizotifen in the canine basilar artery system appears to be calcium channel blockade and not selective antagonism of serotonin or norepinephrine. Calcium channel blocking ability may be related to the clinical efficacy of pizotifen in the treatment of migraine.

Animals↗
PubMed1985

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced dopamine D2 receptor hypersensitivity in the mouse is transient.

Adult C57 B1 mice were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using two dosage regimens. Following a 20 mg/kg/hour X 4 schedule, the number of dopamine D2 receptors labeled by 3H-spiperone was significantly increased at 2 days following the last injection of MPTP (124 +/- 8.0% of control values; p less than 0.025). Scatchard analysis revealed an increase in the number of 3H-spiperone binding sites. No significant difference between the control and MPTP treated animals could be detected in 3H-spiperone binding at 4 and 6 days following the short term MPTP treatment. Similarly, a regimen of 30 mg/kg/day X 10 MPTP caused a transient increase in 3H-spiperone binding to dopamine D2 receptors (1 day: 143 +/- 12%, p less than 0.01; 10 days: 101 +/- 3.7%, p greater than 0.05). These results suggest that MPTP does not produce permanent supersensitivity of dopamine D2 receptors in the mouse.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

Autoradiographic localization of 5-HT1 receptors to human and canine basilar arteries.

Autoradiographic techniques were used to identify serotonergic binding sites in human and canine basilar artery segments. 5-HT1, but not 5-HT2, receptors could be localized to the medial layer of the vascular wall using both [3H]LSD and [3H]5-HT. The identification of 5-HT1 binding sites in human and canine basilar arteries provides anatomical evidence that the 5-HT1 receptor mediates vasoconstriction in these major intracranial vessels.

Animals↗
PubMed1984

5-HT1 receptor sites and functional correlates.

Radioligand techniques have identified at least two distinct serotonergic binding sites in the central nervous system; "5-HT1" sites have high affinity for serotonin and related agonists and low affinity for serotonergic antagonists. Similar pharmacological properties are present in a number of physiological systems, including stimulation of adenylate cyclase, inhibition of neurotransmitter release and contraction of certain arterial systems. The correlation between binding data and physiological functions allows these sites to be designated "5-HT1 receptors".

Adenylyl Cyclases↗
PubMed1984

The calcium antagonist properties of cyproheptadine: implications for antimigraine action.

Cyproheptadine is equipotent (IC50 = 41 to 45 nM) in blocking contractions of canine basilar artery segments induced by serotonin, norepinephrine, potassium, or calcium. Methysergide and amitriptyline display variable potencies in inhibiting contractions depending on the initiating agent. Propranolol, at concentrations to 10 micromolar, had minimal effect on vessel contractions. We conclude that the primary action of cyproheptadine in preventing induced contractions of the canine basilar artery is antagonism of calcium channels. This action is unique among drugs used for migraine prophylaxis and may have important implications for the treatment of headache and other neurologic disorders.

Animals↗
PubMed1983

Serotonin-induced contraction of canine basilar artery: mediation by 5-HT1 receptors.

Serotonin and related agonists cause a marked contraction of canine basilar artery segments. These contractions can be inhibited by a variety of serotonergic antagonists. Absolute potencies of both serotonin agonists and antagonists in chamber contraction studies significantly correlate (P less than 0.01) with their potencies for 5-HT1, but not 5-HT2, receptors as defined by central nervous system radioligand binding studies. Serotonin-induced contractions of canine basilar artery segments appear to be mediated by 5-HT1 receptors.

Animals↗
PubMed1983

Calcium channel antagonist binding sites labeled by 3H-nimodipine in human brain.

In vitro binding of 3H-nimodipine to human brain membranes is demonstrated in this study. This binding was specific and saturable, and had an apparent affinity constant (KD) of 0.27 nM. The maximal number of binding sites for 3H-nimodipine was 5.8 pmoles/gm wet weight of human frontal cortex. The binding was shown to be dependent on calcium, with half-maximal stimulation obtained at 3 X 10(-5) M CaCl2. Other 1,4-dihyropyridine calcium antagonists were shown to be competitive antagonists of 3H-nimodipine binding. In contrast, the calcium antagonists, verapamil and diltiazem, had complex interactions with 3H-nimodipine binding. These results represent the first identification of 3H-calcium antagonist binding sites in human brain, and they confirm that various calcium antagonist drugs may differ with respect to both their potency and their molecular site of action.

Binding Sites↗