Selective antiaggressive effects of alnespirone in resident-intruder test are mediated via 5-hydroxytryptamine1A receptors: A comparative pharmacological study with 8-hydroxy-2-dipropylaminotetralin, ipsapirone, buspirone, eltoprazine, and WAY-100635.
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The present study characterized the effects of the novel, selective, and potent 5-hydroxytryptamine1A (serotonin) (5-HT1A) receptor agonist, alnespirone [S-20499, (S)-N-4-[5-methoxychroman-3-yl)propylamino)butyl- 8-azaspiro-(4,5)-diacetamide, hydrochloride] on offensive and defensive resident-intruder aggression in wild-type rats and compared its actions with those of the prototypical full 5-HT1A agonist 8-hydroxy-2- dipropylaminotetralin (8-OH-DPAT), the partial 5-HT1A agonists ipsapirone and buspirone, and the mixed 5-HT1A/1B agonist eltoprazine. All five agonists exerted effective dose-dependent decreases of offensive aggressive behavior in resident rats; 8-OH-DPAT was the most potent (ID50 = 0.074 mg/kg), followed by eltoprazine (0.24), buspirone (0.72), ipsapirone (1.08), and alnespirone (1.24). However, in terms of selectivity of the antiaggressive effects as determined by the absence of decrements in social interest and general motor activity, alnespirone appeared to be superior. In the defensive aggression test, neither alnespirone nor any of the other four agonists changed defensive behaviors in the intruder rats. The involvement of 5-HT1A receptors in the antiaggressive actions of these drugs was confirmed by showing that the selective 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride), which was inactive alone, fully prevented the antiaggressive effects of alnespirone, 8-OH-DPAT, and buspirone and partly reversed those of ipsapirone and eltoprazine. The data clearly indicate that alnespirone effectively suppresses offensive aggression with an advantageous profile of action compared with other full or partial 5-HT1A agonists. These selective antiaggressive actions of alnespirone are mediated by stimulating 5-HT1A receptors, presumably the somatodendritic autoreceptors at the raphe nuclei. Furthermore, the data provide evidence for a major involvement of these 5-HT1A receptors in the modulation of aggressive behavior by 8-OH-DPAT, ipsapirone, buspirone, and eltoprazine. (+info)
[3H]-Mesulergine labels 5-HT7 sites in rat brain and guinea-pig ileum but not rat jejunum.
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1. The primary aim of this investigation was to determine whether binding sites corresponding to the 5-HT7 receptor could be detected in smooth muscle of the rat jejunum. Binding studies in rat brain (whole brain minus cerebellum) and guinea-pig ileal longitudinal muscle were also undertaken in order to compare the binding characteristics of these tissues. Studies were performed using [3H]-mesulergine, as it has a high affinity for 5-HT7 receptors. 2. In the rat brain and guinea-pig ileum, pKD values for [3H]-mesulergine of 8.0 +/- 0.04 and 7.9 +/- 0.11 (n = 3) and Bmax values of 9.9 +/- 0.3 and 21.5 +/- 4.9 fmol mg(-1) protein were obtained respectively, but no binding was detected in the rat jejunum. [3H]-mesulergine binding in the rat brain and guinea-pig ileum was displaced with the agonists 5-carboxamidotryptamine (5-CT) > 5-hydroxytryptamine (5-HT) > or = 5-methoxytryptamine (5-MeOT) > sumatriptan and the antagonists risperidone > or = LSD > or = metergoline > ritanserin > > pindolol. 3. Despite the lack of [3H]-mesulergine binding in the rat jejunum, functional studies undertaken revealed a biphasic contractile response to 5-HT which was partly blocked by ondansetron (1 microM). The residual response was present in over 50% of tissues studied and was found to be inhibited by risperidone > LSD > metergoline > mesulergine = ritanserin > pindolol, but was unaffected by RS 102221 (3 microM), cinanserin (30 nM), yohimbine (0.1 microM) and GR 113808 (1 microM). In addition, the agonist order of potency was 5-CT > 5-HT > 5-MeOT > sumatriptan. 4. In conclusion, binding studies performed with [3H]-mesulergine were able to detect 5-HT7 sites in rat brain and guinea-pig ileum, but not in rat jejunum, where a functional 5-HT7-like receptor was present. (+info)
Increased transcriptional activity of prostate-specific antigen in the presence of TNP-470, an angiogenesis inhibitor.
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Prostate-specific antigen, PSA, is regarded as a reliable surrogate marker for androgen-independent prostate cancer (AIPC). Concern has been raised that investigational agents may affect PSA secretion without altering tumour growth or volume. In a phase I trial, several patients with AIPC had elevated serum PSA levels while receiving TNP-470 that reversed upon discontinuation. TNP-470 inhibits capillary growth in several angiogenesis models. These observations prompted us to determine if TNP-470, or its metabolite, AGM-1883, altered PSA secretion. Intracellular protein and transcriptional levels of PSA and androgen receptor were also determined. The highest TNP-470 concentration produced a 40.6% decrease in cell number; AGM-1883 had minimal effects on cell viability. PSA secretion per cell was induced 1.1- to 1.5-fold following TNP-470 exposure. The same trend was observed for AGM-1883. PSA and AR were transcriptionally up-regulated within 30 min after exposure to TNP-470. PSA transcription was increased 1.4-fold, while androgen receptor (AR) transcription was induced 1.2-fold. The increased PSA transcriptional activity accounts for the increased PSA secretion. Increased AR transcription was also reflected at the protein level. In conclusion, TNP-470 and AGM-1883 both up-regulated PSA making clinical utilization of this surrogate marker problematic. (+info)
Pharmacological diversity between native human 5-HT1B and 5-HT1D receptors sited on different neurons and involved in different functions.
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The releases of [3H]5-hydroxytryptamine ([3H]5-HT) and of endogenous glutamic acid and their modulation through presynaptic h5-HT1B autoreceptors and h5-HT1D heteroreceptors have been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery. The inhibition by 5-HT of the K+ (15 mM)-evoked overflow of [3H]5-HT was antagonized by the 5-HT1B/5-HT1D receptor ligand GR 127935, which was ineffective on its own; this drug was previously found to behave as a full agonist at the h5-HT1D heteroreceptor regulating glutamate release. The recently proposed selective h5-HT1B receptor ligand SB-224289 also prevented the effect of 5-HT at the autoreceptor, being inactive on its own; in contrast, SB-224289, at 1 microM, was unable to interact with the h5-HT1D heteroreceptor. The inhibitory effect of 5-HT on the K+-evoked overflow of glutamate was antagonized by the h5-HT1D receptor ligand BRL-15572; added in the absence of 5-HT the compound was without effect. BRL-15572 (1 microM) was unable to modify the effect of 5-HT at the autoreceptor regulating [3H]5-HT release. The selective 5-HT1A receptor antagonist (+)-WAY 100135, previously found to be an agonist at the h5-HT1D heteroreceptor regulating glutamate release, could not interact with the h5-HT1B autoreceptor when added at 1 microM. It is concluded that native h5-HT1B and h5-HT1D receptors exhibit a hitherto unexpected pharmacological diversity. (+info)
Neurologically active plant compounds and peptide hormones: a chirality connection.
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The most dramatic, but seldom mentioned, difference between alkaloid and peptide opioids is the change of chirality of the alpha carbon of the tyramine moiety. We propose that the presence of Gly2 or D-Ala2 in the two most common message domains compensates this change by allowing the attainment of unusual conformations. A thorough conformational search of Tyr-D-Ala-Phe-NH-CH3 and of its isomer Tyr-L-Ala-Phe-NH-CH3 backs this view and establishes a solid link between alkaloid and peptide opioids. This finding supports the notion that morphine, like other neurologically active plant compounds, may bind to endogenous receptors in plants to regulate cell-to-cell signaling systems. (+info)
The effect of miotics on the intraocular pressure of conscious owl monkeys.
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The intraocular pressure of conscious, unsedated owl monkeys (Aotus trivirgatus) was measured with an applanation tonometer. Untreated eyes of the conscious animals were found to have higher values than those reported for owl monkeys anesthetized with pentobarbitone. Locally applied pilocarpine, carbachol, and oxotremorine gave concentration-related reduction in pressure, oxotremorine being the most potent and having longer duration of effect than the other compounds. Slight reductions were also observed with aceclidine and R. S. 86. These results are discussed in relation to the effects of miotics in man. (+info)
Aspirochlorine: a highly selective and potent inhibitor of fungal protein synthesis.
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Aspirochlorine, a compound belonging to the gliotoxin family of compounds, exhibits antifungal and antibacterial activity but its mechanism of action remains unknown. In this study we show that aspirochlorine inhibits the pathogenic fungus Candida albicans by acting on fungal protein synthesis. The compound selectively inhibits cell-free protein synthesis when using a C. albicans system, but does not inhibit this synthesis in vitro when tested with bacterial and mammalian systems. Moreover, in intact C. albicans cells, aspirochlorine inhibits protein synthesis but does not inhibit chitin, DNA or glucan synthesis though at high concentrations some inhibition of RNA synthesis is observed. By contrast, in intact Bacillus subtilis cells, aspirochlorine did not inhibit protein, DNA, or cell wall synthesis though it significantly inhibited RNA synthesis. Furthermore, using heterologous systems (mammalian ribosomes and C. albicans cytosolic factors) the data suggest that the inhibitory action of aspirochlorine is not exerted through a direct interaction with C. albicans EF-1 or EF-2. (+info)
V1a- and V2-type vasopressin receptors mediate vasopressin-induced Ca2+ responses in isolated rat supraoptic neurones.
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1. The pharmacological profile of receptors activated by vasopressin (AVP) in freshly dissociated supraoptic magnocellular neurones was investigated using specific V1a- and V2-type AVP receptor agonists and antagonists. 2. In 97 % of AVP-responding neurones (1-3000 nM) V1a or V2 receptor type agonists (F-180 and dDAVP, respectively) elicited dose-dependent [Ca2+]i transients that were suppressed by removal of external Ca2+. 3. The [Ca2+]i response induced by 1 microM F-180 or dDAVP was selectively blocked by 10 nM of V1a and V2 antagonists (SR 49059 and SR 121463A, respectively). The response to V1a agonist was maintained in the presence of the V2 antagonist, and the V2 agonist-induced response persisted in the presence of the V1a antagonist. 4. The [Ca2+]i response induced by 1 microM AVP was partially (61 %) blocked by 10 nM SR 121463A. This blockade was increased by a further 31 % with the addition of 10 nM SR 49059. Similarly, the AVP-induced response was partially (47 %) decreased by SR 49059, and a further inhibition of 33 % was achieved in the presence of SR 121463A. 5. We demonstrate that AVP acts on the magnocellular neurones via two distinct types of AVP receptors that exhibit the pharmacological profiles of V1a and V2 types. However, since V2 receptor mRNA is not expressed in the supraoptic nucleus (SON), and since V1b receptor transcripts are observed in the SON, we propose that the V2 receptor agonist and antagonist act on a 'V2-like' receptor or a new type of AVP receptor that remains to be elucidated. The possibility that V2 ligands act on the V1b receptor cannot be excluded. (+info)