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Pharmacological characterization of RP 62203, a novel 5-hydroxytryptamine 5-HT(2) receptor antagonist
1 RP 62203 (2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8-cd]isothiazole-1, 1-dioxide) is a novel naphtosultam derivative which shows very high affinity for 5-HT(2) receptors in the rat cerebral cortex (K(i) = 50.0 pM). 2 RP 62203 is relatively selective for this sub-type of 5-hydroxytrypta...
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| Main Authors: | , , , , , , , , , , |
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| Formato: | Artigo |
| Idioma: | English |
| Publicado em: |
1992
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| Assuntos: | |
| Acesso em linha: | https://ncbi.nlm.nih.gov/pmc/articles/PMC1908636/ https://ncbi.nlm.nih.gov/pubmed/1596688 |
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| Resumo: | 1 RP 62203 (2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8-cd]isothiazole-1, 1-dioxide) is a novel naphtosultam derivative which shows very high affinity for 5-HT(2) receptors in the rat cerebral cortex (K(i) = 50.0 pM). 2 RP 62203 is relatively selective for this sub-type of 5-hydroxytryptamine (5-HT) receptor, having lower affinity for the 5-HT(1A) receptor and very low affinity for the 5-HT(3) receptor. RP 62203 displayed low to moderate affinity for α(1)-adrenoceptors, dopamine D(2) receptors and histamine H(1) receptors. 3 In vivo binding experiments demonstrated that oral administration of low doses of RP 62203 led to a long-lasting (>6h) occupation of cortical 5-HT(2) receptors (ID(50) = 0.39 mg kg(-1)). 4 In cortical slices from the neonatal rat, RP 62203 potently inhibited inositol phosphate formation evoked by 5-HT, with an IC(50) of 7.76 nM. 5 The activity of neurones in the raphé and their responses to microiontophoretically applied 5-HT were studied with extracellular recording electrodes in the anaesthetized rat. RP 62203 potently and dose-dependently blocked excitations evoked by 5-HT when administered at doses of 0.5–4.0 mg kg(-1), i.p. In contrast, neither 5-HT-evoked depressions nor glutamate-evoked excitations of raphé neuronal firing were blocked by RP 62203 at doses as high as 8.0 mg kg(-1), i.p. 6 Head twitches induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) could be abolished by low doses of RP 62203 in mice (ED(50) = 0.44 mg kg(-1), p.o.) and in rats (ED(50) = 1.54 p.o.). Similar results were obtained with mescaline and 5-hydroxytryptophan (5-HTP). 7 The potency of RP 62203 was compared with that of three other 5-HT(2) receptor antagonists, ritanserin, ICI 169,369 and ICI 170,809. In all models, RP 62203 showed similar activity to ritanserin, whilst either ICI 169,369 or ICI 170,809 was several fold less active. 8 It is concluded that RP 62203 is a potent and selective antagonist at 5-HT(2) receptors in the rodent central nervous system. |
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