5-HT2B Agonist Research Articles

Ligand functional selectivity advances our understanding of drug mechanisms and drug discovery

‘Intrinsic efficacy' (the concept that a drug acting at a single receptor is always an agonist, partial agonist, or antagonist/inverse agonist) had been accepted for a half-century. Two decades ago, it became clear that a single G protein-coupled receptor (GPCR) could have promiscuous G protein interactions. This suggested that some drugs might cause differential effects on signaling via a single receptor, and within a few years, there were data showing such ‘anomalous' functional responses—in the extreme, a ligand acting at a single receptor being a full agonist at one function and an antagonist at another (Kilts et al, 2002). Strikingly, most laboratories engaged with this phenomenon recognized its implications, each proffering a unique name (eg, agonist-directed trafficking of signaling, biased agonism, etc), with functional selectivity emerging as the apparent consensus. The naming quandary, the involved mechanisms, the impact on understanding drug action, the relevance to drug discovery, and even the implications for teaching have been reviewed recently (Urban et al, 2007), now including the first book on the subject (Neve, 2009). It appears that this is a universal phenomenon for all GPCRs and other drug targets, and that many drugs may cause such differential signaling. The question is whether functional selectivity is an interesting artifact for the specialist, or a mechanism that affects psychoactive drug action and drug discovery. The data suggest that both are true (Kilts et al, 2002; Smith et al, 1997). As an example, a recent publication examined the impact of functional selectivity on valvulopathy, which was thought to be due to 5-HT2B agonist-induced mitogenic action in the heart. Clinical drugs were selected for their 5-HT2B agonist profile in traditional assays, and then functionally profiled. Of this group, ropinirole was differentiated from the other compounds by its signaling profile, possibly explaining why it has a decreased risk of valvulopathy (Huang et al, 2009). To our knowledge, this is the first example for the differentiated side-effect profiles of functional selectivity. Of direct neuropsychopharmacological relevance is the dopamine mechanism of action of aripiprazole. The most commonly disseminated hypothesis is that aripiprazole causes ‘dopamine stabilization' through D2 partial agonism. Conversely, other data have shown that aripiprazole, although sometimes a partial agonist, can also be a D2 pure antagonist or full agonist depending on the assay system. As we have reviewed recently (Mailman, 2007), the original in vivo/ex vivo data from the drug's discoverers are consistent with D2 functional selectivity, but not with simple partial agonism. Functional selectivity would thus predict that D2 ligands selected as partial agonists in a single common functional assay may not be similar clinically. From this perspective, the failure of preclamol or bifeprunox to have adequate antipsychotic efficacy may not be surprising. The level of complexity added by functional selectivity also provides opportunity. In the short term, it permits a greater understanding of the differential neuropsychopharmacology of drugs once thought to be functionally similar, and may permit discrimination of potential drug candidates. In the long term, scientific advances showing how individual signaling pathways affect cellular function (and subsequent physiological responses) will provide a mechanistic foundation for the discovery of rationally chosen functionally selective drugs.

Wishing Away Inflammation? New Links between Serotonin and TNF Signaling

Wishing Away Inflammation? New Links between Serotonin and TNF Signaling

Serotonergic drugs and valvular heart disease

Background: The serotonin (5-HT) releasers (±)-fenfluramine and (+)-fenfluramine were withdrawn from clinical use owing to increased risk of valvular heart disease. One prevailing hypothesis (i.e., the ‘5-HT hypothesis’) suggests that fenfluramine-induced increases in plasma 5-HT underlie the disease. Objective: Here, we critically evaluate the possible mechanisms responsible for fenfluramine-associated valve disease. Methods: Findings from in vitro and in vivo experiments performed in our laboratory are reviewed. The data are integrated with existing literature to address the validity of the 5-HT hypothesis and suggest alternative explanations. Conclusions: The overwhelming majority of evidence refutes the 5-HT hypothesis. A more likely cause of fenfluramine-induced valvulopathy is activation of 5-HT2B receptors on heart valves by the metabolite norfenfluramine. Future serotonergic medications should be designed to lack 5-HT2B agonist activity.

Pergolide and valvular heart disease: the lower the better?

Recently, several publications have confirmed the association between pergolide use and valvular heart disease (VHD).1–3 The serotonin 2B (5HT2b) receptor has been proposed as the key pathway through which pergolide and other drugs activate valvular fibroblasts to proliferate and to produce myxoid substance and collagen, leading to valvular thickening and insufficiency.4 This can explain the occurrence of VHD with 5HT2b agonists such as pergolide and cabergoline, while drugs without 5HT2b activity have not been reported to cause valvulopathy (i.e. pramipexole, lisuride). These recent findings have led to the voluntary withdrawal of pergolide in the US (mars 2007) and to an increased awareness of, and recommendations for a more careful use of pergolide by neurologists in Europe. The studies that reported an association between pergolide and VHD were mainly conducted in older patients with Parkinson's disease who usually require higher dosages of pergolide compared with patients with restless leg syndrome or hyperprolactinemia. Even at low dose, pergolide remains also useful for many …

Possible Involvement of Endogenous 5-HT in Aggravation of Cerulein-Induced Acute Pancreatitis in Mice

The aim of the present study was to elucidate the pathogenic role of endogenous 5-HT in pancreatitis. Injections of cerulein at hourly intervals caused edematous pancreatitis in mice characterized by hyperenzymemia and histological alterations. While the cerulein-induced hyperenzymemia was attenuated in mice pretreated with p-CPA, a 5-HT depletor, it was exaggerated by the preferential 5-HT2A agonist (DOI), but not by the preferential 5-HT2B agonist (BW723C86) or the preferential 5-HT2C agonist (mCPP). Selective 5-HT2A antagonists (risperidone, spiperone, ketanserin, AMI-193, and MDL 11,939) dose-dependently attenuated the hyperenzymemia; and their potency order, excepting that of ketanserin which has considerable affinity at the 5-HT2C receptor as well, paralleled their reported pKi values at the 5-HT2A receptor. Selective 5-HT2B (SB204741) and 5-HT2C (SB242084) antagonists hardly affected the hyperenzymemia. Although the non-selective 5-HT2A/2B/2C antagonists (metergoline, ritanserin, and methysergide) dose-dependently attenuated the hyperenzymemia, they were relatively less potent compared to their high pKi values at the 5-HT2A receptor. In another set of experiments, risperidone, but not SB204741 and SB242084, dose-dependently reversed the cerulein-induced histological alteration of the pancreas (inflammatory cell infiltration). These results suggest that endogenously released 5-HT activates 5-HT2A receptors to aggravate cerulein-induced pancreatitis. We propose that selective 5-HT2A antagonists may provide a new therapy for acute pancreatitis.

Serotonin-induced contraction in mesenteric resistance arteries: signaling and changes in deoxycorticosterone acetate-salt hypertension.

Large arteries from hypertensive subjects are hyperresponsiveness to 5-hydroxytryptamine (5-HT). We tested the hypothesis that small arteries (225 micro ID) have a profile similar to conduit arteries, including signal transduction mechanisms and the 5-HT receptor subtype(s) mediating arterial contraction in normal and high blood pressure. Aorta and mesenteric arteries from Sprague-Dawley (232+/-6 micro ID), sham (229+/-7 micro ID; systolic blood pressure, 120+/-2 mm Hg), or deoxycorticosterone acetate (DOCA)-salt rats (255+/-11 micro ID, 192+/-8 mm Hg) were mounted in a wire-based myograph. In resistance arteries from Sprague-Dawley rats, the 5-HT2A receptor mediated contraction; agonists of the 5-HT1B, 5-HT1D, 5-HT1F, and 5-HT2B receptor were inactive. The tyrosine kinase inhibitor genistein (5 micromol/L, 4.8-fold rightward shift), PD 098,059 (10 micromol/L, 3.2-fold shift), phospholipase C inhibitor NCDC (100 micromol/L), and nifedipine (50 nmol/L) reduced maximum 5-HT-induced contraction in small arteries (4.5% and 53% control, respectively). As in aorta, 5-HT had a decrease in threshold (100-fold lower), increase in potency (11.6-fold leftward shift), and increase in efficacy (140% sham response) in small arteries from DOCA-salt rats compared with sham. Unlike in aorta, 5-HT-induced contraction in DOCA-salt small arteries was shifted competitively by the 5-HT2A receptor antagonist ketanserin (-log K(B) [mol/L] for both sham and DOCA-salt, 9.25+/-0.1), and contraction to the 5-HT2B agonist BW723C86 was not observed. Thus, the 5-HT2A receptor remains the contractile receptor in hypertension in small arteries. Although similarities were observed for large and small arteries, differences under the condition of DOCA-salt hypertension exist that may determine serotonergic compounds effective in lowering blood pressure.

Antinociceptive Effects of Intrathecal 5-Hydroxytryptamine and Its Subtype Agonists in the Formalin Test

Background: Although 5-hydroxytryptamine (5-HT) is involved in the modulation of nociceptive transmission in the spinal cord, the effect of it is not clear. Previous studies have revealed the presence of many types of 5-HT receptors in the spinal cord. The aim of this study was to determine the role of spinal serotonergic receptors by examination of the effects of intrathecal 5-HT and its subtype agonists on the stimulus evoked by formalin injection. Methods: Rats were implanted with lumbar intrathecal catheters. Intrathecal 5-HT and its subtype agonists were administered 10 min before the formalin injection. After the formalin injection, a formalin-induced nociceptive behavior (flinching response) was observed for 60 min. Results: Intrathecal administration of 5-HT, 5-HT agonist (dipropyl-5CT), 5-HT agonist (CGS- 12066A), 5-HT2 agonist (-methyl-5-HT), 5-HT2B agonist (BW723C86), 5- agonist (MK 212), 5-HT agonist (m-CPBG) and 5-agonist (BZTZ) produced a dose-dependent suppression of flinches in both phases. However, neither 5-HT agonist (GR 46611) nor 5-HT>agonist (BRL 54443) reduced the flinches in either phase. Conclusions: Spinal 5-HT, 5-HT, 5-HT, 5-HT, 5-HT, 5-HT and 5-HT receptors may be involved in the regulation of a nociceptive state evoked by a formalin stimulus, whereas spinal 5-HT, 5-HT and 5-HTreceptors may not be involved.

Mediation by 5-hydroxytryptamine2B receptors of endothelium-dependent relaxation in rat jugular vein.

1. An 'atypical' 5-HT2 receptor which is located on the endothelium of rat jugular vein has been described. In the present study we have further defined the nature of the 5-HT2 receptor subtype present in this preparation. 2. In experiments conducted in the presence of ketanserin to preclude involvement of 5-HT2 receptors, the mixed 5-HT2B/2C antagonist, SB 200646, acted as an antagonist of 5-HT at the endothelial 5-HT receptor (pA2 = 7.2). Yohimbine, which exhibits negligible affinity for rat 5-HT2C receptors but has high 5-HT2B receptor affinity, acted as a potent but non-surmountable antagonist (pA2 > or = 7.3) in rat jugular vein. Neither yohimbine nor SB 200646 affected endothelium-dependent relaxations induced by carbachol. 3. Mianserin also acted as a surmountable antagonist (pA2 = 7.3) and the 5-HT2B agonist, BW 723C86, acted as a potent partial agonist (pEC50 [95% C L], intrinsic activity +/- s.e. mean = 7.9 [7.6-8.3], 0.84 +/- 0.04). Responses to BW 723C86 were antagonized by SB 200646 (0.3 microM) yielding an 'apparent' pA2 [95% CL] of 7.03 [6.76-7.32]. 4. These data are consistent with the presence of 5-HT2B receptors mediating endothelium-dependent relaxation of rat jugular vein.

The pseudo-affective reflex of pagani-sherrington as screening test for serotoninergic drugs

The feeding effects of 5-hydroxytryptamine (5-HT)1 and 5-HT2 receptor agonists injected into the hypothalamic paraventricular nucleus (PVN) immediately prior to PVN administration of neuropeptide Y (NPY) were examined. The impact of these same compounds on NPY-induced alterations in energy metabolism was also assessed in an attempt to characterize further the potential interactive relationship of PVN NPY and 5-HT on feeding and whole body calorimetry. Specifically, several experiments examined the effect of various 5-HT receptor agonists on NPY-stimulated eating and alterations in energy substrate utilization [respiratory quotient (RQ)]. This included the 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B/1A agonist RU 24969, the 5-HT1D agonist L-694,247, the 5-HT2A/2C agonist DOI, the 5-HT2B agonist BW 723C86 and the 5-HT2C agonist mCPP. In feeding tests conducted at the onset of the dark cycle, drugs were administered 5 min prior to PVN injection of NPY and food intake was measured 2 h postinjection. The metabolic effects of NPY following a similar pretreatment were monitored using an open-circuit calorimeter measuring the volume of oxygen consumed (VO2), carbon dioxide produced (VCO2) and RQ (VCO2/VO2). PVN injection of NPY (100 pmol) potentiated feeding and evoked reliable increases in RQ. Only DOI (2.5–5 nmol) pretreatment antagonized NPY-induced eating and blocked the peptide's effect on energy substrate utilization. Direct PVN pretreatment with spiperone (SPRN), a 5-HT2A receptor antagonist, and ketanserin (KTSN), a 5-HT2A/2C antagonist, but not SDZ SER 082, a 5-HT2B/2C antagonist, or the 5-HT2C antagonist RS 102221, blocked the effect of DOI in both feeding and metabolic tests providing additional evidence that activation of PVN 5-HT2A receptors inhibits NPY's action on feeding and substrate utilization.