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S J Peroutka

Publications and source records attributed to S J Peroutka.

At least 73 records · Page 4Linked to original sources
PubMed1990

Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes.

Affinities of drugs for 21 indolealkylamine derivatives, some with putative hallucinogenic activity, were determined at 5-HT1A, 5-HT2A and 5-HT2B recognition sites, using radioligand competition studies. Nearly all of the derivatives displayed greatest potency for the 5-HT2A receptor, labelled by [125I]R-(-)DOI in the cortex of the rat. Most derivatives displayed 2-10 times lower affinity at the HT2B receptor labelled by [3H]ketanserin in bovine cortex. Derivatives lacking ring substituents displayed lower affinities for all of the recognition sites, compared to derivatives substituted in the 4- or 5-position of the indole ring. The 4-hydroxylated derivatives displayed 25-380-fold selectivity for the 5-HT2A site, vs the 5-HT1A site, while the 5-substituted derivatives displayed approximately equal potency at the 5-HT1A and 5-HT2A sites. Affinity of all the compounds at the 5-HT2B site was greater than 300 nM. The 6-substituted derivatives displayed greater than micromolar affinities for all of the 5-HT recognition sites examined. The size of the N,N-dialkyl substituent was a secondary determinant of affinity, with groups larger than N,N-diisopropyl resulting in a marked reduction in affinity at both the 5-HT2A and 5-HT1A recognition sites. This study demonstrated that hallucinogenic 4-hydroxy-indolealkylamines, like psychotomimetic phenylisopropylamines, bind potently and selectively to the 5-HT2A recognition site, labelled by [125I]R-(-)DOI. This provides further evidence indicating that this recently described subtype of the 5-HT2 receptor may partially mediate the action of hallucinogenic agents.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

In vivo effects of sumatriptan (GR 43175) on extracellular levels of 5-HT in the guinea pig.

The effect of sumatriptan, a selective 5-HT1D receptor agent, on extracellular levels of 5-HT in the frontal cortex of the guinea pig was measured by intracerebral dialysis. A constant infusion of sumatriptan (10(-8)-10(-7) M) dose-dependently reduced extracellular levels of 5-HT (e.g. 80 +/- 2% decrease from control levels of 5-HT at 10(-7) M). Peripheral administration of sumatriptan (50 micrograms/kg i.p. and 500 micrograms/kg i.p.) had no effect on extracellular levels of 5-HT in the frontal cortex. These data suggest that sumatriptan, when infused into the brain, inhibits the release of 5-HT by stimulating 5-HT autoreceptors and that the putative acute anti-migraine effects of sumatriptan are likely to be mediated by peripheral mechanisms.

Animals↗
PubMed1990

d-Lysergic acid diethylamide differentially affects the dual actions of 5-hydroxytryptamine on cortical neurons.

5-Hydroxytryptamine (5-HT; 10(-4) M) produces an initial depolarization, followed by a long-lasting hyperpolarization, when focally applied to pyramidal neurons in the somatosensory cortex of the rat. Application of the selective 5-HT1A agonist, 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT; 10(-6) M) or d-lysergic acid diethylamide (d-LSD; 10(-6) M), produced only a hyperpolarizing response which was larger than the response to 5-HT. Application of 8-OH-DPAT (10(-6) M) and 5-HT (10(-4) M) together produced an initial depolarizing response, similar to the response with 5-HT alone, followed by a hyperpolarizing response which was 23 +/- 3% larger than with 5-HT alone. By contrast, the application of d-LSD (10(-6) M) and 5-HT (10(-4) M) together produced either no depolarization (7 of 13 cells) or a significantly smaller depolarizing response (36 +/- 4% of the response to 5-HT alone), as well as a hyperpolarizing response which was 33 +/- 4% larger than with 5-HT alone. Therefore, d-LSD displayed a unique pharmacological ability to both mimic and block the effect of 5-HT on single neurons in somatosensory cortex of the rat.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Modulation of 5-hydroxytryptamine1A receptor density by nonhydrolyzable GTP analogues.

Co-incubation of rat cortical membranes with 10(-4) M GTP results in a competitive inhibition of 5-hydroxytryptamine1A (5-HT1A) receptor binding sites labeled by [3H]8-hydroxy-2-(di-n-propylamino)tetralin [( 3H]8-OH-DPAT). Preincubation of cortical membranes with 10(-4) M GTP does not significantly change either KD or Bmax values, indicating that the effect of GTP is reversible. By contrast, GTP gamma S and 5'-guanylylimidodiphosphate (GppNHp) are nonhydrolyzable analogues of GTP which lengthen the time course of guanine nucleotide activation of guanine nucleotide binding proteins (G proteins) and thereby alter G protein-receptor interactions. These nonhydrolyzable GTP analogues were used to characterize the effects of persistent alterations in G proteins on [3H]8-OH-DPAT binding to 5-HT1A receptors. Co-incubation of rat cortical membranes with either 10(-4) M GTP gamma S or GppNHp results in a decrease in both the affinity and apparent density of 5-HT1A binding sites. Co-incubation with the nonhydrolyzable nucleotides reduces the affinity of [3H]8-OH-DPAT binding by 65-70% and lowers the density of the binding site by 53-61%. Similarly, preincubation of membranes with a 10(-4) M concentration of either GTP gamma S or GppNHp significantly increases the KD value and reduces the Bmax value of [3H]8-OH-DPAT binding. These results indicate that GTP gamma S and GppNHp induce persistent changes in 5-HT1A receptor-G protein interactions that are reflected as a decrease in the density of binding sites labeled by [3H]8-OH-DPAT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

The pharmacology of current anti-migraine drugs.

The major finding of this analysis is that acute anti-migraine agents (e.g., ergots, sumatriptan) share high affinity for 5-HT1D receptors. This receptor appears to be present in certain intracranial blood vessels. It is also found on nerve terminals where it inhibits the release of 5-HT and other neurotransmitters. Theoretically, 5-HT1D receptor agonists may acutely inhibit the release of vasoactive and/or pain-inducing substances in the perivascular space. Conceivably, drugs acting at this receptor would stop the progression of this perivascular process. In contrast, a number of prophylactic anti-migraine drugs share a relatively high affinity for 5-HT2 receptors in human brain. Although this receptor is also found in certain blood vessels, it is present throughout the nervous system. The receptor appears to mediate neuronal depolarizations at the cellular level. No hypothesis, at present, readily explains the effectiveness of prophylactic anti-migraine drugs based on this receptor. These data offer a novel approach to the analysis of anti-migraine agents. Drugs could be selected for use in clinical migraine studies based on their selectivity for a specific 5-HT receptor subtype. "Pure" drugs could be chosen which would essentially limit the number of possible sites of action for the drugs. For example, an agent which displays both high affinity and selectivity for 5-HT1D receptors could be clinically evaluated. Its effectiveness, or lack thereof, would indicate the importance of the specific 5-HT receptor site in the pathogenesis of migraine. Further attempts to determine a common mechanism of action for effective anti-migraine agents should facilitate the elucidation of the pathogenesis of this neurological syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1990

Sumatriptan in acute migraine: pharmacology and review of world experience.

The introduction of sumatriptan, a novel abortive antimigraine agent, has generated a significant amount of preclinical and clinical interest during the past few years. At the scientific level, sumatriptan is unique in terms of its selective pharmacological properties. The effects of sumatriptan in various experimental paradigms have led to new insights into the pathophysiology of migraine. At the clinical level, sumatriptan appears to be an effective abortive anti-migraine agent with minimal side effects. Its ability to decrease, rather than exacerbate, the nausea and vomiting of migraine appears to be an important advance in the treatment of migraine.

Acute Disease↗
PubMed1990

5-Hydroxytryptamine receptor subtypes.

Significant advances in the molecular pharmacological analysis of 5-hydroxytryptamine (5-HT) receptor subtypes occurred in the 1980's. To a significant degree, this progress resulted from 2 independent approaches: molecular biology and molecular pharmacology. This review focuses on the pharmacological data derived from radioligand binding studies. At the present time, 5-HT receptor subtypes are often categorized into at least 3 major "families" as well as a few "orphan" receptors that cannot yet be placed into the major categories. Each "family" consists of multiple receptor subtypes which share similarities in their molecular biological, pharmacological, biochemical and physiological properties. In order to provide a comparative pharmacological analysis of the 7 most extensively characterized 5-HT receptor subtypes, potency information is presented on the 30 pharmacological agents that have been, to date, studied most extensively in the published literature.

Amino Acid Sequence↗
PubMed1990

Receptor "families" for 5-hydroxytryptamine.

Significant advances in the analysis of 5-hydroxytryptamine (5-HT) receptor subtypes occurred in the 1980s. Although the current status of 5-HT receptor pharmacology may appear confusing to many investigators, the evolving data suggest that 5-HT receptor subtypes can be categorized into three major "families." Each "family" consists of multiple receptor subtypes that share similarities in their molecular, biological, pharmacological, biochemical, and/or physiological properties. These receptor subtypes are present throughout the nervous system as well as in the periphery. A simple framework for the classification of 5-HT receptor subtypes is provided in the present review.

Animals↗
PubMed1990

Serotonin receptor and reuptake sites: pharmacologic significance.

The past decade has seen important advances in the clinical use of serotonergic agents. The authors summarize the current status of selective agents for 5-HT receptor subtypes and their utility in the treatment of human neuropsychiatric disorders. The putative novel anxiolytic effects of 5-HT1A partial agonists such as buspirone, the unique and potent antiemetic effects of 5-HT3 antagonists in cancer chemotherapy, and the antidepressant effects of selective 5-HT uptake blockers such as fluoxetine are excellent examples of the clinical relevance of selective 5-HT receptor agents. The increasing ability to modulate serotonergic neurotransmission via distinct serotonin (5-HT) receptor subtypes should greatly facilitate the analysis of the role of 5-HT in both normal and abnormal human brain function.

Brain↗
PubMed1990

Quantitative molecular analysis predicts 5-hydroxytryptamine3 receptor binding affinity.

A quantitative molecular model was derived to predict drug affinities for 5-hydroxytryptamine3 (5-HT3) receptors. The model was based on the molecular characteristics of a "learning set" of 40 pharmacological agents that had been analyzed previously in radioligand binding studies. Molecules were analyzed for various structural features, i.e., the presence of a benzenoid ring and nitrogen atom, substitutions on the benzenoid ring, the location of the substitutions on the nitrogen, and the molecular characteristics of the most direct pathway from the benzenoid ring to the nitrogen. Weighting factors, based on published 5-HT3 receptor affinity data, were then assigned to each of 10 molecular characteristics. The derived computational model predicts accurately the affinities of the learning set for the 5-HT3 receptor (r = 0.98; p less than 0.001). The computational model was then used to predict the receptor affinities of a "test set" of 40 pharmacological agents. The predicted values for these agents also correlate significantly (r = 0.83; p less than 0.001) with drug affinities for the 5-HT3 receptor, as determined by radioligand binding assays. This first line screening approach allows for the accurate prediction of drug affinities based on molecular characteristics with minimal dependence upon animal tissues or radioactivity.

Animals↗
PubMed1990

Developments in 5-hydroxytryptamine receptor pharmacology in migraine.

Because a satisfactory animal model for migraine does not exist, attempts to determine a common mechanism of action for effective antimigraine agents may be of benefit in elucidating the pathogenesis of this neurologic syndrome. The present review demonstrates that the clinical data that has developed over the past 30 years may allow for the elucidation of the role of specific 5-HT receptor subtypes in the pathophysiology of migraine. A large number of both acute and prophylactic antimigraine agents share an ability to interact with 5-HT receptor subtypes in human brain. As summarized in Table 3, acute antimigraine drugs (e.g., ergots, sumatriptan) share high affinity for 5-HTID receptors and somewhat lower affinity for 5-HT1A receptors. These receptors are present in certain intracranial blood vessels. 5-HT1D receptors are also located on nerve terminals where they act to inhibit the release of 5-HT and other neurotransmitters. Theoretically, 5-HTID receptor agonists may acutely inhibit the release of vasoactive or pain-inducing substances in the perivascular space. Conceivably, drugs acting at this receptor would stop the progression of this perivascular process. In addition, a number of prophylactic antimigraine drugs display a relatively high affinity for both 5-HT2 and 5-HT1C receptors in human brain. Although these receptors are also found in certain blood vessels, they are present throughout the nervous system. The receptors appear to mediate neuronal depolarizations at the cellular level. Moreover, the 5-HT2 receptor appears to play a key role in the development of inflammation in certain smooth muscle systems. Theoretically, the ability of 5-HT2 antagonists to protect perivascular inflammation may account for their efficacy in the prophylactic treatment of migraine. These data offer a novel approach to the analysis of antimigraine agents. Drugs could be selected for use in clinical migraine studies based on their selectivity for a specific 5-HT receptor subtype. For example, an agent that displays both high affinity and selectivity for 5-HT1D receptors could be clinically evaluated. Its effectiveness, or lack thereof, would indicate the importance of this specific 5-HT receptor site in the pathogenesis of migraine. Future attempts to determine a common mechanism of action for effective antimigraine agents should facilitate the elucidation of the pathogenesis of this neurologic syndrome.

Brain↗
PubMed1989

Reserpine does not prevent 3,4-methylenedioxymethamphetamine-induced neurotoxicity in the rat.

3,4-Methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a known neurotoxin to 5-hydroxytryptamine (5-HT) nerve terminals. Recent studies have suggested that endogenous dopamine (DA) and/or 5-HT may mediate the MDMA-induced neurotoxicity. The central monoamine stores of rats were significantly decreased with reserpine (5 mg/kg) prior to toxic injections of MDMA. Rats given MDMA (30 mg/kg) displayed significant decreases in the density of 5-HT nerve terminals labeled by [3H]paroxetine both with (51 +/- 8%) and without (43 +/- 20%) reserpine pre-treatment. These data suggest that the degeneration of 5-HT nerve terminals following MDMA is independent of the presence of endogenous stores of DA or 5-HT.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Binding of arylpiperazines to 5-HT3 serotonin receptors: results of a structure-affinity study.

The binding affinities of a series of arylpiperazine derivatives at [3H]quipazine-labeled central 5-HT3 sites were investigated. Features determined to be important for binding include the N4 piperazine nitrogen atom (but not the N1 piperazine nitrogen), and a quinolinyl group. The quinoline nitrogen atom of quipazine also contributes to affinity and its replacement by carbon reduces affinity by 20-fold. The entire quinoline nucleus is not necessary for binding, and certain monocyclic arylpiperazines, particularly those with a chloro group meta to the position of the piperazine ring (e.g. mCPP, MK-212), also bind at 5-HT3, sites; however, the affinities of these agents are at least an order of magnitude less than that of quipazine itself. Taking advantage of the fact that tertiary amines are not well tolerated at 5-HT1B sites, but that N-methyl substituents have little effect on 5-HT3 binding, we designed and synthesized a tertiary amine analog of quipazine, i.e., N-methylquipazine (NMQ). NMQ binds at 5-HT3 sites with an affinity similar to that of quipazine; however, unlike quipazine, NMQ shows very little affinity (IC50 greater than 10,000 nM) for central 5-HT1B sites.

Animals↗