Flesinoxan

Wouters, Wout; Hartog, J. P. Den; Bevan, Paul

doi:10.1111/j.1527-3466.1988.tb00373.x

Cited by 22 publications

(10 citation statements)

References 9 publications

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“…Furthermore, the present in vivo data show a selective inhibition of the dose-response relationship of the blood pressure lowering effect of A-74283 in conscious SHR after treatment with spiroxatrine, or BMY 7378, putative 5HT 1A antagonists [21]. Thus, data obtained from the present study using A-74283 indicate an important role of the 5HT 1A receptor mechanism for the control of blood pressure in the cardiovascular system, confirming the previous suggestion made by others using flesinoxan [8,9] or urapidil [30,31].…”

Section: Discussionsupporting

confidence: 81%

“…In particular, the 5HT 1A receptor subtype exerts significant control over the cardiovascular system [7]. For example, activation of Lee/Hancock/Warner/Brune/Meyer/ DeBernardis the central 5HT 1A receptor decreases arterial blood pressure in experimental hypertension and thus, offers a novel approach to the control of hypertension [8][9][10]. In our effort to develop 5HT 1A selective agents from radioligand binding studies, a series of compounds of the hexahydro-benz(e)isoindole class was discovered to possess a high degree of selectivity for the 5HT 1A receptor.…”

Section: Introductionmentioning

confidence: 99%

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Cardiovascular Activity of A-74283, a 5-Hydroxytryptamine<sub>1A</sub> Agent, in the Spontaneously Hypertensive Rat

Lee¹,

Hancock²,

Warner³

et al. 1998

Pharmacology

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A-74283, (+,-)trans-2-(4-(3a,4,4a,6a,7,7a-hexahydro-4,7-etheno-1H cyclobut [f] isoindol-1,3-dionyl)-butyl)-9-methoxy-2,2,2a,4,5,9b-hexahydro-1H-benz[e]isoindol HCl, was studied in receptor binding assays and in the spontaneously hypertensive rat (SHR). In radioligand binding to rat cortex, A-74283 had high affinity (equipotent to 8-OH-DPAT) and high selectivity for 5HT_1A receptors compared to 5HT_1B sites. In conscious SHR, A-74283 lowered mean arterial pressure (MAP) in a dose-related fashion with a prolonged effect after oral administration of higher doses, but heart rate (HR) was not changed. In anesthetized SHR, i.v. administration of A-74283 decreased MAP and total peripheral resistance, but not cardiac output. Pretreatment of conscious SHR with the selective 5TH_1A receptor antagonists spiroxatrine or BMY 7378 reduced the hypotensive effect of A-74283 significantly, but pretreatment with adrenergic antagonists phenoxybenzamine or idazoxan or the 5HT₂ receptor blocker ketanserin did not alter the effect of A-74283. Intracisternal administration of A-74283 also decreased MAP; however, A-74283 had no effect on blood pressure in pithed SHR in which blood pressure was supported with vasopressin, in contrast to nitroprusside. These data demonstrate that A-74283 exerts a potent hypotensive effect in SHR via systemic vasodilation originating from a central 5HT_1A receptor mechanism. A-74283 may be useful for studying 5HT_1A receptors and cardiovascular function.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Cardiovascular Activity of A-74283, a 5-Hydroxytryptamine<sub>1A</sub> Agent, in the Spontaneously Hypertensive Rat

Lee¹,

Hancock²,

Warner³

et al. 1998

Pharmacology

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“…As anxiolytic compounds we chose the benzodiazepines (BZD) diazepam and alprazolam (Chouinard et al 1982), the full 5-HT 1A receptor agonists flesinoxan (Wouters et al 1988;Bradford 1993) and 8-OH-DPAT (Engel et al 1984), the partial 5-HT 1A receptor agonists buspirone (Goa and Ward 1986) and BMY 7378 (Yocca et al 1987), and alcohol. As mixed anxiolytic-antidepressants we tested the 5-HT uptake inhibitors fluvoxamine (Claassen et al 1977, Den Boer et al 1987) and clomipramine (McTavish and Benfield 1990) and the MAO inhibitor clorgyline (Tyrer and Shawcross 1988).…”

Section: Introductionmentioning

confidence: 99%

Reduction of guinea pig pup isolation calls by anxiolytic and antidepressant drugs

et al. 1996

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Guinea pigs possess central 5-HT1D receptors similar to humans but different from rats and mice. In order to study the role of this receptor on animal behaviour, it may be of interest to develop a paradigm measuring affective states in the guinea pig. Therefore we assessed the effects of a variety of psychotropic drugs on guinea pig pup isolation calls. Anxiolytic compounds such as the benzodiazepine receptor agonists diazepam and alprazolam, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, and alcohol reduced isolation calling by the guinea pig pup. Moreover, mixed antidepressant/anxiolytic compounds like the 5-HT uptake inhibitors fluvoxamine and clomipramine or the MAO-inhibitor clorgyline as well as the antidepressant NA uptake inhibitors desipramine and maprotiline suppressed vocalizations. The 5-HT1D/1A receptor agonist 5-CT was also very effective in reducing separation calls. Remarkably, the partial 5-HT1A receptor agonists buspirone and BMY 7378 did not affect calling. The neuroleptic haloperidol, the psychostimulant d-amphetamine, the putative anxiogenics DMCM and m-CPP and the putative anxiolytics ondansetron and CI-988 had no effect on isolation calls of guinea pig pups. We propose this paradigm could be helpful to assess behavioural effects of anxiolytic and antidepressant drugs in a species different from rat or mouse, and in which the effects of 5-HT1D receptor ligands may possibly be established.

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“…Studies in rats showed similar activity for flesinoxan (Wouters et al, 1988). Little is known however about the influence of 5-HT1A agonists on body temperature after chronic administration.…”

Section: Introductionmentioning

confidence: 68%

Pilot study of flesinoxan, a 5‐HT1A agonist, in major depression: Effects on sleep REM latency and body temperature

Ansseau

Pitchot

Moreno

et al. 1993

Human Psychopharmacology

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Flesinoxan is a highly potent and selective 5-HTlA full agonist, active in several models of depression. In this pilot open study, flesinoxan (4 mdd) was administered orally for 4 weeks in 16 major depressive, mostly treatmentresistant inpatients exhibiting a score of at least 19 on the Hamilton depression sale. Weekly ratings included Hamilton depression scale, Montgomery and Asberg depression scale (MADRS), and Clinical Global Impressions (CGI). Results showed considerable improvement in depressive symptomatology, with mean MADRS scores (SD) dropping from 35.7 (10.0) to 13.0 (11.9) and CGI-illness severity from 5.69 (1.14) to 2.73 (1.62) after 4 weeks of treatment. Moreover, 13 patients were classified as much or very much improved on the CGI-global improvement. The tolerance of flesinoxan was excellent, with only four patients exhibiting side-effects. In contrast to acute studies with 5HTlA agonists, flesinoxan induced no significant decrease in daily oral temperature over the Cweek period.In eight melancholic patients, the mean REM latency (SD) of respectively 35.6 (15.9) and 40.2 (17.9) min during two baseline nights significantly increased to 51-9 (20-9) min during a double-blind challenge night with flesinoxan 1 mg as compared to 42.0 (16.1) min with placebo, and to respectively 55.6 (29.9) and 55.6 (30.2) min during the last two treatment nights. All these findings encourage further developments of flesinoxan as a promising antidepressant.woms-Flesinoxan, 5-HTl A agonists, antidepressant, major depression, REM latency, body temperature.

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Flesinoxan

Cited by 22 publications

References 9 publications

Cardiovascular Activity of A-74283, a 5-Hydroxytryptamine<sub>1A</sub> Agent, in the Spontaneously Hypertensive Rat

Cardiovascular Activity of A-74283, a 5-Hydroxytryptamine<sub>1A</sub> Agent, in the Spontaneously Hypertensive Rat

Reduction of guinea pig pup isolation calls by anxiolytic and antidepressant drugs

Pilot study of flesinoxan, a 5‐HT1A agonist, in major depression: Effects on sleep REM latency and body temperature

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