Fananserin

A bridging study of fananserin in schizophrenic patients.[Pubmed:10513457]

Psychopharmacol Bull. 1998;34(4):811-8.

Fananserin is a potential antipsychotic compound with high affinity for both D4 and 5-HT2A receptors, and negligible affinity for D2 receptors. Because the tolerance for antipsychotic compounds often differs between schizophrenic patients and healthy subjects, this bridging study was designed to evaluate the tolerability of Fananserin, to define the slow titration maximum tolerated dose in the target population, and to identify the most rapid well-tolerated rate of titration for this compound. Three rates of titration regimens were examined in a total of 26 schizophrenic patients in a parallel group design, following a 3-day placebo washout period from previous antipsychotic medication. The slow rate of titration (reaching the maximum dose of 600 mg/day in 16 days with 100-mg increases every 3 days) was well tolerated, but a rapid titration schedule (reaching 600 mg/day in 8 days with 200-mg increases every 3 days) resulted in hypotension in 3 of 6 patients and termination of the group on Day 10. An intermediate rate of titration (reaching 600 mg/day in 10 days with 100-mg increases every 2 days) was then examined and was well tolerated, with transient episodes of mild hypotension reported in 2 of 10 patients. Thus, although hypotension was identified as the dose-limiting adverse event in this study, a reduction in the titration rate was effective in reducing the incidence and severity of this side effect. In this study, schizophrenic patients administered multiple doses of Fananserin tolerated doses 400 percent greater than the maximum tolerated single dose in healthy volunteers.

The naphtosultam derivative RP 62203 (fananserin) has high affinity for the dopamine D4 receptor.[Pubmed:8957240]

Eur J Pharmacol. 1996 Oct 24;314(1-2):229-33.

The dopamine D4 receptor is a potential target for novel antipsychotic drugs. Most available compounds with affinity for the dopamine D4 receptor also bind to dopamine D2 receptors. This report describe the affinity of the 5-HT2A receptor antagonist RP 62203 (Fananserin) for the human dopamine D4 receptor. Fananserin displaces [3H]spiperone binding to recombinant human dopamine D4 receptors with a Ki of 2.93 nM. This compares with an affinity (Ki) of 0.37 nM for the rat 5-HT2A receptor and of 726 mM for the rat dopamine D2 receptor. [3H]Fananserin can be used to label the recombinant dopamine D4 receptor expressed in Chinese hamster ovary cells with a KD of 0.725 nM. Fananserin is, thus, the first compound to be reported that distinguishes between dopamine D4 and D2 receptors.

Placebo-controlled study of the D4/5-HT2A antagonist fananserin in the treatment of schizophrenia.[Pubmed:10080558]

Am J Psychiatry. 1999 Mar;156(3):419-25.

OBJECTIVE: The authors' objective was to assess the potential efficacy of Fananserin (RP62203), a potent antagonist at the D4 and serotonin2A (5-HT2A) receptors, on symptoms of schizophrenia. METHOD: A double-blind, placebo-controlled study was conducted in 97 patients. Doses of Fananserin reached 250 mg b.i.d. over 28 days, starting with an 8-day escalation. Most of the patients were men with paranoid schizophrenia; they were approximately 38 years old. The primary outcome measure was the total Positive and Negative Syndrome Scale score. The patients' mean score on the Positive and Negative Syndrome Scale at entry was 91.8 (SD=16.5). A low dropout rate was observed in both groups of patients (19 [30%] of those given Fananserin and nine [27%] of those given placebo). RESULTS: The total Positive and Negative Syndrome Scale score of the patients given Fananserin decreased at endpoint by a mean of 4.2 points (SD=15.4); the score of the patients given placebo decreased by 6.7 points (SD=19.6). No differences between treatments were found on secondary measures such as the Clinical Global Impression, Positive and Negative Syndrome Scale subscores or individual items, and Brief Psychiatric Rating Scale total score. The patients' extrapyramidal symptoms did not worsen during the trial, but the patients given Fananserin had an increase in akathisia. The safety profile was good in both groups of patients. CONCLUSIONS: The results of this study do not support the prediction that a selective D4 antagonist associated with strong 5-HT2A antagonism will exhibit an antipsychotic effect.

Pharmacological characterization of RP 62203, a novel 5-hydroxytryptamine 5-HT2 receptor antagonist.[Pubmed:1596688]

Br J Pharmacol. 1992 Jan;105(1):27-36.

1. RP 62203 (2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8- ca]isothiazole-1,1-dioxide) is a novel naphtosultam derivative which shows very high affinity for 5-HT2 receptors in the rat cerebral cortex (Ki = 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-HT1A receptor and very low affinity for the 5-HT, receptor. RP 62203 displayed low to moderate affinity for alpha 1-adrenoceptors, dopamine D2 receptors and histamine H1 receptors. 3. In vivo binding experiments demonstrated that oral administration of low doses of RP 62203 led to a long-lasting (greater than 6 h) occupation of cortical 5-HT2 receptors (ID50 = 0.39 mgkg-1). 4. In cortical slices from the neonatal rat, RP 62203 potently inhibited inositol phosphate formation evoked by 5-HT, with an IC50 of 7.76 nM. 5. The activity of neurones in the raphe 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 raphe 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 (ED50 = 0.44 mg kg-1, p.o.) and in rats (ED50 = 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-HT2 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-HT2 receptors in the rodent central nervous system.

Naphthosultam derivatives: a new class of potent and selective 5-HT2 antagonists.[Pubmed:1908521]

J Med Chem. 1991 Aug;34(8):2477-83.

A series of 2-(aminoalkyl)naphth[1,8-cd]isothiazole 1,1-dioxides was synthesized and examined in various receptor binding tests. Most compounds demonstrated high affinity for the 5-HT2 receptor with moderate to high selectivity. A member of this series, compound 24 (RP 62203), displays high 5-HT2 receptor affinity (Ki = 0.26 nM), which is respectively more than 100 and 1000 times higher than its affinity for alpha 1 (Ki = 38 nM) and D2 (Ki greater than 1000 nM) receptors. This compound is a potent orally effective and long lasting 5-HT2 antagonist in the mescaline-induced head-twitches test in mice and rats.

Fananserin (RP 62203) is an orally bioavailable, potent and selective 5-hydroxytryptamine2 (5-HT2) receptor antagonist, with a Ki of 0.37 nM for the rat 5-HT2A receptor. Fananserin also is a selective dopamine D4 receptor antagonist, with a Ki of 2.93 nM for the human dopamine D4 receptor.

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