Altanserin hydrochloride

Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET.[Pubmed:19329329]

Bioorg Med Chem. 2009 Apr 15;17(8):2989-3002.

Radiolabelled piperidine derivatives such as [(11)C]MDL 100907 and [(18)F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with (18)F-fluorine, were synthesized to improve molecular imaging properties of [(11)C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show K(i)-values in the nanomolar range towards the 5-HT(2A) receptor and insignificant binding to other 5-HT receptor subtypes or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antagonistic (18)F-tracers for visualization of the 5-HT(2A) receptor status. Medium affine compounds (VK-1 (32), (51), (52), (54)) were synthesized and have K(i) values between 30 and 120 nM. All promising compounds show logP values between 2 and 3, that is, within the range of those for the established radiotracers altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be promising high affine and selective tracers of (18)F-labelled analogues for 5-HT(2A) imaging with PET.

Evidence that 5-HT2c receptor antagonists are anxiolytic in the rat Geller-Seifter model of anxiety.[Pubmed:7846211]

Psychopharmacology (Berl). 1994 Feb;114(1):90-6.

Four non-selective 5-HT2C/5-HT2A receptor antagonists, mianserin (2-8 mg/kg), 1-naphthyl piperazine (1-NP) (0.5-1 mg/kg), ICI 169,369 (20 mg/kg) and LY 53857 (5 mg/kg), increased punished responding for a food reward in the rat Geller-Seifter test 30 min after subcutaneous (SC) administration. This property was shared by the benzodiazepine anxiolytic chlordiazepoxide (5 mg/kg SC). However, the selective 5-HT2A receptor antagonists ketanserin (0.2-1 mg/kg SC) and altanserin (0.5, 1 mg/kg SC) had little effect. The 5-HT1A, 5-HT1B and beta-adrenergic receptor antagonists pindolol and cyanopindolol (6 mg/kg SC) did not affect punished responding either, nor did the 5-HT1D receptor partial agonist and alpha 2 adrenergic receptor antagonist yohimbine (2.5 mg/kg SC) or the histamine H1 receptor antagonist mepyramine (1 mg/kg SC). Unpunished responding was also modestly increased after some doses of the 5-HT2C/5-HT2A receptor antagonists. However, this effect was inconsistent and was also seen after chlordiazepoxide. Furthermore, it was not associated with the increase in punished responding observed in rats orally treated with mianserin (10, 20 mg/kg), 1-NP (10, 20 mg/kg) or ICI 169,369 (50 mg/kg). The action of the 5-HT2C/5-HT2A receptor antagonists tested is therefore consistent with anxiolysis. The results also strongly suggest that this effect is mediated by blockade of the 5-HT2C receptor, although the possibility of 5-HT2B receptor mediation is discussed.

Stimulation of corticosterone and beta-endorphin secretion in the rat by selective 5-HT receptor subtype activation.[Pubmed:2956114]

Eur J Pharmacol. 1987 May 7;137(1):1-8.

Changes in plasma concentrations of corticosterone and beta-endorphin (beta-END) were determined in male rats after treatment with the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or the non-selective 5-HT agonist 6-chloro-2-(1-piperazinyl)pyrazine (MK-212). The administration of either 8-OH-DPAT or MK-212 increased plasma concentrations of both corticosterone and beta-END in a dose-related manner. The corticosterone and beta-END responses to 8-OH-DPAT were antagonized by spiperone and (-)-pindolol, both of which have been shown to have high affinity for the 5-HT1A binding site. In contrast, antagonist which are selective for the 5-HT2 receptor or non-selective 5-HT antagonists were without effect on the hormone responses to 8-OH-DPAT. The MK-212-induced increase in plasma concentrations of corticosterone and beta-END were not affected by treatment with the 5-HT1A antagonists spiperone and (-)-pindolol. However, the corticosterone and beta-END responses to MK-212 were attenuated by the selective 5-HT2 antagonists ketanserin, ritanserin and altanserin, as well as by the non-selective 5-HT antagonist metergoline. It is concluded that stimulation of either 5-HT1A or 5-HT2 receptors results in an activation of the hypothalamic-pituitary-adrenal axis in the rat.

Involvement of 5-HT2 receptors in the LSD- and L-5-HTP-induced suppression of lordotic behavior in the female rat.[Pubmed:3872342]

J Neural Transm. 1985;61(1-2):65-80.

Copulatory behavior in the ovariectomized rat, the lordotic response (L.R.), was induced by estrogen followed by progesterone. L.R. is inhibited by lysergic acid diethylamide (LSD) (greater than or equal to 0.05 mg/kg) and by Levo-5-hydroxytryptophan (L-5-HTP) (greater than or equal to 2.5 mg/kg). The effects of the putative 5-HT antagonists lisuride, metergoline, methysergide, mianserin, cinanserin, cyproheptadine, pirenperone and altanserin on the LSD-induced inhibition of L.R. were tested. Lisuride, metergoline, methysergide and mianserin were found to have no LSD-blocking effect. In contrast, cinanserin, cyproheptadine and pirenperone acted antagonistically to LSD, within a critical dose range. The selective 5-hydroxytryptamine2 (5-HT2) receptor antagonist altanserin effectively prevented the LSD-induced inhibition of L.R., and the doses required (0.05-0.20 mg/kg) indicated a comparatively high antagonistic potency. In addition altanserin (0.2 mg/kg) effectively prevented the lordosis inhibitory effect induced by L-5-HTP (2.5 mg/kg), after pretreatment with pargyline and RO4-4602. It is suggested that the suppression of copulatory behavior caused by LSD and L-5-HTP is mediated by 5-HT2 receptors.