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Agonist Properties (agonist + property)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

5-HT1A RECEPTOR AGONIST PROPERTIES OF ANTIPSYCHOTICS DETERMINED BY [35S]GTP,S BINDING IN RAT HIPPOCAMPAL MEMBRANES

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2007
Yuji Odagaki
SUMMARY 15-Hydroxytryptamine 1A (5-HT1A) receptors have attracted increasing attention as a promising target for antipsychotic therapy. Although many atypical antipsychotic drugs, including the prototype clozapine, have been reported to be partial agonists at 5-HT1A receptors, these results are often fragmental and derived mainly from experiments that used cultured cells. 2In the present study, [35S]guanosine 5,- O -(3-thiotriphosphate) ([35S]GTP,S) binding assay in rat hippocampal membranes was applied to a series of antipsychotic drugs, especially atypical antipsychotics. 3Most, but not all, of atypical antipsychotic drugs and the classical antipsychotic drug nemonapride behaved as partial agonists at 5-HT1A receptors with varied potencies and relative efficacies. The most potent compound was perospirone with a mean EC50 of 27 nmol/L, followed by aripiprazole (45 nmol/L) > ziprasidone (480 nmol/L) > nemonapride (790 nmol/L) > clozapine (3900 nmol/L) > quetiapine (26 000 nmol/L). The maximal percentage increases over the basal binding (%Emax) for these antipsychotic drugs were 30,50%, with the exception of perospirone (, 15%), whereas 5-HT stimulated the binding to a mean %Emax of 105%. 4Increasing concentrations of the selective and neutral 5-HT1A antagonist WAY100635 shifted the concentration,response curve of nemonapride-stimulated [35S]GTP,S binding to the right and in parallel. 5The relative efficacy or intrinsic activity of a compound was affected differently by the differing concentrations of guanosine diphosphate (GDP) in the assay buffer, which should be taken into consideration when determining the relative efficacies of these antipsychotics as 5-HT1A receptor agonists. 6These results provide important information concerning the relevance of 5-HT1A receptor partial agonist properties in the treatment for schizophrenic patients with most, if not all, of atypical antipsychotic drugs. [source]

Effect of caffeine on prospective and retrospective duration judgements

HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2003
Ronald P. Gruber
Abstract The effects of caffeine on prospective and retrospective duration judgements were evaluated in a double-blind placebo-controlled experiment. After taking either 200,mg caffeine or a placebo, participants touched a 17-sided polygon for 15,s. Then they verbally estimated the number of angles and the duration. Participants in the prospective group were told in advance they would be making a duration estimate, whereas those in the retrospective group were not told. Caffeine reduced duration estimates in the prospective condition but not in the retrospective condition. The effect of caffeine on very long duration comparisons (the past year compared with a year at one-half and one-quarter of one's age) was also evaluated, but none was found. The findings do not support the hypothesis that caffeine affects duration experience by increasing the internal clock rate as a result of its dopamine D2 agonist properties. The hypothesis that caffeine produces its effect by enhancing memory was considered and rejected. The most parsimonious explanation is that caffeine increased arousal level, which led to a narrowing of the focus of attention to the most salient task. Copyright © 2003 John Wiley & Sons, Ltd. [source]

Dualistic actions of cromakalim and new potent 2H -1,4-benzoxazine derivatives on the native skeletal muscle KATP channel

BRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2003
Domenico Tricarico
New 2H -1,4-benzoxazine derivatives were synthesized and tested for their agonist properties on the ATP-sensitive K+ channels (KATP) of native rat skeletal muscle fibres by using the patch-clamp technique. The novel modifications involved the introduction at position 2 of the benzoxazine ring of alkyl substituents such as methyl (,CH3), ethyl (,C2H5) or propyl (,C3H7) groups, while maintaining pharmacophore groups critical for conferring agonist properties. The effects of these molecules were compared with those of cromakalim in the presence or absence of internal ATP (10,4M). In the presence of internal ATP, all the compounds increased the macropatch KATP currents. The order of potency of the molecules as agonists was ,C3H7 (DE50=1.63 × 10,8M) >,C2H5 (DE50=1.11 × 10,7M)>,CH3 (DE50=2.81 × 10,7M)>cromak-slim (DE50= 1.42 × 10,5M). Bell-shaped dose,response curves were observed for these compounds and cromakalim indicating a downturn in response when a certain dose was exceeded. In contrast, in the absence of internal ATP, all molecules including cromakalim inhibited the KATP currents. The order of increasing potency as antagonists was cromakalim (IC50=1.15 × 10,8M),CH3 (IC50=2.6 × 10,8M)>,C2H5 (IC50=4.4 × 10,8M)>,C3H7 (IC50=1.68 × 10,7M) derivatives. These results suggest that the newly synthesized molecules and cromakalim act on muscle KATP channel by binding on two receptor sites that have opposite actions. Alternatively, a more simple explanation is to consider the existence of a single site for potassium channel openers regulated by ATP which favours the transduction of the channel opening. The alkyl chains at position 2 of the 2H -1,4-benzoxazine nucleus is pivotal in determining the potency of benzoxazine derivatives as agonists or antagonists. British Journal of Pharmacology (2003) 139, 255,262. doi:10.1038/sj.bjp.0705233 [source]