Sabcomeline (SB-202026), a functionally selective M1 receptor partial agonist, reverses delay-induced deficits in the T-maze

 Sabcomeline, (SB-202026 [R-(Z)-α-(methoxyimino)-1-azabicyclo [2.2.2] octane-3-acetonitrile]), a functionally selective muscarinic M₁ receptor partial agonist, was tested in rats trained to perform a delayed, reinforced alternation task in a T maze, a test of short-term spatial memory. For comparison the cholinesterase inhibitor tacrine (THA-9-amino-1,2,3,4-tetrahydroaminoacridine) and the non-selective muscarinic receptor agonist RS86 (2-ethyl-8-methyl-2,8 diazospiro [4.5]-decane-1,3-dione hydrobromide) were also tested and all three compounds were also compared using a conditioned taste aversion (CTA) task. Sabcomeline (0.001–1.0 mg/kg IP) significantly reversed the T-maze choice accuracy deficit induced by a 20-s delay at 0.03 and 0.1 mg/kg. RS86 (0.1–3.0 mg/kg IP) reversed the deficit at 1.0 mg/kg and THA (0.1–3.0 mg/kg IP) had no effect at any dose. All three compounds induced conditioned taste aversion with minimum effective doses (MED) of 0.3, 1.0 and 3.0 mg/kg, respectively. The results show that sabcomeline reverses delay induced deficits in T-maze choice accuracy in a rewarded alternation task at doses approximately 10 times lower than those required to induce conditioned taste aversion. RS86 was equipotent in both tests. These data support the findings of clinical studies which have shown that SB-202026 provides significant symptomatic improvement in patients with probable Alzheimer’s disease at doses which do not induce cholinergic side effects. Received: 19 August 1997 / Final version: 14 January 1998     

SDZ ENS 163 is a selective M1 agonist and induces release of acetylcholine

Summary In the present study some pharmacological properties of the new muscarinic agonist SDZ ENS 163; (+)-(3S,cis)-3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl)methyl-2(3H)-thiophenonedihydrogenphosphate] have been investigated. In the rat superior cervical ganglion, a model for M₁ muscarinic receptors, SDZ ENS 163 induced concentration-dependent depolarizations (pD₂ = 6.5 ± 0.3; efficacy = 128 ± 4.2% compared to carbachol). SDZ ENS 163 was a very weak partial agonist with respect to M₂ receptor-induced decrease in contractile force in rat left atria (efficacy = 14 ± 2.9%). In addition, SDZ ENS 163 competitively antagonized the effect of carbachol in rat left atria (pA₂ = 5.8 ± 0.2). In the guinea-pig ileum SDZ ENS 163 was a partial agonist with respect to force of contraction mediated by M₃ receptors (pD₂ = 5.3 ± 0.1; efficacy = 72 ± 4.2%). The oxotremorine-induced inhibition of the electrically stimulated release of acetylcholine (ACh) in rat hippocampal slices was reversed by SDZ ENS 163 (pA₂ = 5.5 ± 0.1). In addition after oral administration SDZ ENS 163 (3 – 10 mol/kg) reduced brain ACh levels, which is indicative of increased ACh turnover. Finally, increases in energy of the low frequency band (2–5 Hz) were observed in rat hippocampal EEG after intraperitoneal administration of SDZ ENS 163 (0.3 – 30 mol/kg). We conclude that SDZ ENS 163 is a selective M₁ agonist in vitro with an additional M₂ antagonistic effect. The in vivo effects of SDZ ENS 163 may result both from postsynaptic M₁ agonistic as well as M₂ receptor antagonistic activity. The unique pharmacological profile of SDZ ENS 163 may prove clinically favourable for treatment of cognitive deficits. Send offprint requests to H. W. G. M. Boddeke at the above address     

Rolofylline,an adenosine A1 receptor antagonist,inhibits osteoclast differentiation as an inverse agonist

BACKGROUND AND PURPOSE

Adenosine may be generated by hydrolysis of extracellular nucleotides by ectonucleotidases, including ectonucleoside triphosphate diphosphohydrolase 1 (CD39), ecto-5′-nucleotidase (CD73), nucleotide pyrophosphatase phosphodiesterase 1 (NPP-1) and tissue non-specific alkaline phosphatase (TNAP). Previous work from our laboratory has uncovered a critical role for adenosine A₁ receptors (A₁R) in osteoclastogenesis; blockade or deletion of these receptors diminishes osteoclast differentiation. Interestingly, selective A₁R agonists neither affect basal osteoclastogenesis nor do they reverse A₁R antagonist-mediated inhibition of osteoclastogenesis. In this study, we determined whether ectonucleotidase-mediated adenosine production was required for A₁R antagonist-mediated inhibition, and, when we saw no effect, determined whether A₁R was constitutively activated and the antagonist was acting as an inverse agonist to diminish osteoclast differentiation.

EXPERIMENTAL APPROACH

Osteoclast formation derived from wild-type, CD39 knockout (KO), CD73 KO, NPP-1 KO and TNAP KO mice was examined by tartrate-resistant acid phosphatase staining of receptor activator of NF-κB ligand–macrophage colony-stimulating factor-stimulated osteoclasts and osteoclast gene expression (Ctsk, Acp5, MMP-9 and NFATc1). Intracellular cAMP concentration was determined by elisa.

KEY RESULTS

Rolofylline inhibited osteoclast formation in a dose-dependent manner (IC₅₀ = 20–70 nM) in mice lacking all four of these phosphatases, although baseline osteoclast formation was significantly less in precursors from CD73 KO mice. Rolofylline (1 μM) stimulates cAMP production in bone marrow macrophages by 10.23 ± 0.89-fold.

CONCLUSIONS AND IMPLICATIONS

Based on these findings, we hypothesize that the A₁R is constitutively activated in osteoclast precursors, thereby diminishing basal AC activity, and that A₁R antagonists act as inverse agonists to release A₁R-mediated inhibition of basal AC activity and permit osteoclast differentiation. The constitutive activity of A₁R promotes osteoclast formation and down-regulation of this activity blocks osteoclast formation.     

Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist

Ramelteon (TAK-375) is a novel melatonin receptor agonist currently under investigation for the treatment of insomnia. This study describes the neurochemical and receptor binding characteristics of ramelteon in vitro. Ramelteon showed very high affinity for human MT1 (Mel1a) and MT2 (Mel1b) receptors (expressed in Chinese hamster ovary [CHO] cells), and chick forebrain melatonin receptors (consisting of Mel1a and Mel1c receptors) with Ki values of 14.0, 112, and 23.1 pM, respectively, making the affinities of ramelteon for these receptors 3-16 times higher than those of melatonin. The affinity of ramelteon for hamster brain MT3 binding sites was extremely weak (Ki: 2.65 microM) compared to melatonin's affinity for the MT3 binding site (Ki: 24.1 nM). In addition, ramelteon showed no measurable affinity for a large number of ligand binding sites (including benzodiazepine receptors, dopamine receptors, opiate receptors, ion channels, and transporters) and no effect on the activity of various enzymes. Ramelteon inhibited forskolin-stimulated cAMP production in the CHO cells that express the human MT1 or MT2 receptors. Taken together, these results indicate that ramelteon is a potent and highly selective agonist of MT1/MT2 melatonin receptors.     

Characterization of the recombinant human prostanoid DP receptor and identification of L-644,698, a novel selective DP agonist

1. A human embryonic kidney cell line [HEK 293(EBNA)] stably expressing the human recombinant prostaglandin D₂ (PGD₂) receptor (hDP) has been characterized with respect to radioligand binding and signal transduction properties by use of prostanoids and prostanoid analogues. Radioligand binding studies included saturation analyses, the effects of nucleotide analogues, the initial rate of ligand-receptor association and equilibrium competition assays. In addition, adenosine 3′:5′-cyclic monophosphate (cyclic AMP) generation in response to ligand challenge was also measured, as this is the predominant hDP signalling pathway.
2. L-644,698 ((4-(3-(3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl) propyl) benzoic acid) (racemate)) was identified as a novel ligand having high affinity for hDP with an inhibitor constant (K_i) of 0.9 nM. This K_i value was comparable to the K_i values obtained in this study for ligands that have previously shown high affinity for DP: PGD₂ (0.6 nM), ZK 110841 (0.3 nM), BW245C (0.4 nM), and BW A868C (2.3 nM).
3. L-644,698 was found to be a full agonist with an EC₅₀ value of 0.5 nM in generating cyclic AMP following activation of hDP. L-644,698 is, therefore, comparable to those agonists with known efficacy at the DP receptor (EC₅₀): PGD₂ (0.5 nM), ZK 110841 (0.2 nM) and BW245C (0.3 nM).
4. L-644,698 displayed a high degree of selectivity for hDP when compared to the family of cloned human prostanoid receptors: EP₁ (>25,400 fold), EP₂ (∼300 fold), EP_3-III (∼4100 fold), EP₄ (∼10000 fold), FP (>25,400 fold), IP (>25,400 fold) and TP (>25,400 fold). L-644,698 is, therefore, one of the most selective DP agonists as yet described.
5. PGJ₂ and Δ¹²-PGJ₂, two endogenous metabolites of PGD₂, were also tested in this system and shown to be effective agonists with K_i and EC₅₀ values in the nanomolar range for both compounds. In particular, PGJ₂ was equipotent to known DP specific agonists with a K_i value of 0.9 nM and an EC₅₀ value of 1.2 nM.

     

Pharmacological characterization of FE 201874, the first selective high affinity rat V1A vasopressin receptor agonist

BACKGROUND AND PURPOSE

Distinct vasopressin receptors are involved in different physiological and behavioural functions. Presently, no selective agonist is available to specifically elucidate the functional roles of the V_1A receptor in the rat, one of the most widely used animal models. FE 201874 is a new derivative of the human selective V_1A receptor agonist F180. In this study, we performed a multi-approach pharmacological and functional characterization of FE 201874 to determine whether it is selective for V_1A receptors.

EXPERIMENTAL APPROACH

We modified an available human selective V_1A receptor agonist (F180) and determined its pharmacological properties in cell lines expressing vasopressin/oxytocin receptors (affinity and coupling to second messenger cascades), in an ex vivo model (aorta ring contraction) and in vivo in rats (proliferation of adrenal cortex glomerulosa cells and lactation).

KEY RESULTS

FE 201874 exhibited nanomolar affinity for the rat V_1A receptor; it was highly selective towards the rat V_1B and V₂ vasopressin receptors and behaved as a full V_1A agonist in all the pharmacological tests performed. FE 201874 bound to the oxytocin receptor, but with moderate affinity, and behaved as an oxytocin antagonist in vitro, but not in vivo.

CONCLUSIONS AND IMPLICATIONS

On functional grounds, all the data demonstrate that FE 201874 is the first selective agonist of the rat V_1A receptor isoform available. Hence, FE 201874 may have potential as a treatment for the vasodilator-induced hypotension occurring in conditions such as septic shock and could be the most suitable compound for discriminating between the behavioural effects of arginine vasopressin and oxytocin.     

AC-260584, an orally bioavailable M1 muscarinic receptor allosteric agonist, improves cognitive performance in an animal model

The recent discovery of allosteric potentiators and agonists of the muscarinic M₁ receptor represents a significant advance in the muscarinic receptor pharmacology. In the current study we describe the receptor pharmacology and pro-cognitive action of the allosteric agonist AC-260584. Using in vitro cell-based assays with cell proliferation, phosphatidylinositol hydrolysis or calcium mobilization as endpoints, AC-260584 was found to be a potent (pEC₅₀ 7.6-7.7) and efficacious (90-98% of carbachol) muscarinic M₁ receptor agonist. Furthermore, as compared to orthosteric binding agonists, AC-260584 showed functional selectivity for the M₁ receptor over the M₂, M₃, M₄ and M₅ muscarinic receptor subtypes. Using GTPγS binding assays, its selectivity was found to be similar in native tissues expressing mAChRs to its profile in recombinant systems. In rodents, AC-260584 activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in the hippocampus, prefrontal cortex and perirhinal cortex. The ERK1/2 activation was dependent upon muscarinic M₁ receptor activation since it was not observed in M₁ knockout mice. AC-260584 also improved the cognitive performance of mice in the novel object recognition assay and its action is blocked by the muscarinic receptor antagonist pirenzepine. Taken together these results indicate for the first time that a M₁ receptor agonist selective over the other mAChR subtypes can have a symptomatically pro-cognitive action. In addition, AC-260584 was found to be orally bioavailable in rodents. Therefore, AC-260584 may serve as a lead compound in the development of M₁ selective drugs for the treatment of cognitive impairment associated with schizophrenia and Alzheimer's disease.     

选择性5-羟色胺1F受体激动剂lasmiditan

随着生活节奏的加快,偏头痛的发病率呈逐渐增加的趋势。目前用于治疗偏头痛的药物主要为曲坦类药物,但由于该类药物会使血管收缩,因此对于心脑血管和周围血管疾病患者禁用。曲坦类药物对中重度头痛患者的疗效显著降低。因此,迫切需要开发新的急性期治疗药物。lasmiditan是一种非曲坦类的5-HT1F受体激动剂,多项临床试验研究表明其具有良好的有效性和安全性。主要从lasmiditan的药物概况、相关背景、合成路线、药理作用、临床研究和安全性等方面进行介绍。     

Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid

The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.     

Central muscarinic receptor subtypes involved in pilocarpine-induced salivation, hypertension and water intake

Background and purpose:

Recent evidence has suggested that pilocarpine (ACh receptor agonist) injected peripherally may act centrally producing salivation and hypertension. In this study, we investigated the effects of specific M₁ (pirenzepine), M₂/M₄ (methoctramine), M₁/M₃ (4-DAMP) and M₄ (tropicamide) muscarinic receptor subtype antagonists injected into the lateral cerebral ventricle (LV) on salivation, water intake and pressor responses to peripheral pilocarpine.

Experimental approach:

Male Holtzman rats with stainless steel cannulae implanted in the LV were used. Salivation was measured in rats anaesthetized with ketamine (100 mg per kg body weight) and arterial pressure was recorded in unanaesthetized rats.

Key results:

Salivation induced by i.p. pilocarpine (4 μmol per kg body weight) was reduced only by 4-DAMP (25–250 nmol) injected into the LV, not by pirenzepine, methoctramine or tropicamide at the dose of 500 nmol. Pirenzepine (0.1 and 1 nmol) and 4-DAMP (5 and 10 nmol) injected into the LV reduced i.p. pilocarpine-induced water intake, whereas metoctramine (50 nmol) produced nonspecific effects on ingestive behaviours. Injection of pirenzepine (100 nmol) or 4-DAMP (25 and 50 nmol) into the LV reduced i.v. pilocarpine-induced pressor responses. Tropicamide (500 nmol) injected into the LV had no effect on pilocarpine-induced salivation, pressor responses or water intake.

Conclusions and implications:

The results suggest that central M₃ receptors are involved in peripheral pilocarpine-induced salivation and M₁ receptors in water intake and pressor responses. The involvement of M₃ receptors in water intake and pressor responses is not clear because 4-DAMP blocks both M₁ and M₃ receptors.     

Metabolic and haemodynamic effects and pharmacokinetics of a new selective beta1-adrenoceptor agonist,prenalterol, in man

Summary The metabolic and haemodynamic effects of three intravenous doses (0.5, 1.0 and 4.0 mg) of prenalterol, a selective ₁-adrenoceptor agonist, were studied in 10 healthy male subjects. Plasma levels of prenalterol during the experiments were related to the haemodynamic effects. Prenalterol induced a dose-dependent increase in systolic blood pressure and heart rate. The maximal effects amounted to about 30 mm Hg and 15 beats/min, respectively, after the highest dose (4.0 mg). The diastolic blood pressure fell by a maximum of about 15 mm Hg. The effect of prenalterol on systolic blood pressure and heart rate persisted for about 3 h after the end of the last infusion, whereas that on diastolic blood pressure only lasted for 60 min. Compared with placebo, there was a moderate increase in plasma FFA and glycerol. A small rise in insulin level was also recorded, but no significant change was seen in other metabolic variables — triglycerides, glucose, lactate, pyruvate. Serum potassium tended to decrease and serum sodium was unchanged. The initial distribution of prenalterol was rapid (half-life 7 min) and the overall elimination rate corresponded to a plasma half-life of 2 h. A linear relationship was found between the plasma level of prenalterol and its effects on systolic blood pressure and heart rate.     

Novel N-Substituted Benzimidazolones as Potent,Selective, CNS-Penetrant,and Orally Active M1 mAChR Agonists

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Pharmacokinetics and pharmacodynamics of ponesimod,a selective S1P1 receptor modulator,in the first-in-human study

Aims

This study investigated the tolerability, safety, pharmacokinetics and pharmacodynamics of ponesimod, a novel oral selective sphingosine-1-phosphate (S1P₁) receptor modulator in development for the treatment of auto-immune diseases.

Methods

This was a double-blind, placebo-controlled, ascending, single-dose study. Healthy male subjects received doses of 1–75 mg or placebo control.

Results

Ponesimod was well tolerated. Starting with a dose of 8 mg, transient asymptomatic reductions in heart rate were observed. Ponesimod pharmacokinetics were dose proportional. The median time to maximal concentration ranged from 2.0 to 4.0 h, and ponesimod was eliminated with a mean half-life varying between 21.7 and 33.4 h. Food had a minimal effect on ponesimod pharmacokinetics. Doses of ≥8 mg reduced total lymphocyte count in a dose-dependent manner. Lymphocyte counts returned to normal ranges within 96 h. A pharmacokinetic/pharmacodynamic model was developed that adequately described the observed effects of ponesimod on total lymphocyte counts.

Conclusions

Single doses of ponesimod up to and including 75 mg were well tolerated. The results of this ascending single-dose study indicate an immunomodulator potential for ponesimod and a pharmacokinetic/pharmacodynamic profile consistent with once-a-day dosing.     

Influence of xamoterol,a partial beta1-selective agonist,on physical performance capacity and cardiocirculatory,metabolic and hormonal parameters

Summary In a double-blind, random, cross-over study, 14 healthy male volunteers received xamoterol 200 mg (Corwin; C) twice daily or placebo (P) for two seven-day medication periods to investigate effects on physical performance, cardiocirulatory parameters, metabolism and hormone levels during exercise. An oral glucose tolerance test (OGTT) was also done.C showed a positive inotropic effect up to an exercise intensity of 100 W, corresponding to a heart rate of about 100 beats · min^–1. Chronotropic regulation of the heart remained unchanged, but the increase in systolic blood pressure was more pronounced and the catecholamines behaved as after P. From 150 W onwards, C exhibited beta-blocking properties; heart rate was reduced by up to 8 beats · min^–1; systolic blood pressure remained unchanged; and the catecholamines showed a more pronounced increase than after P. Diastolic blood pressure behaved almost identically under all test conditions.With the exception of a slightly increased level of free fatty acids at rest, the parameters of physical performance, lipid and carbohydrate metabolism and the hormone levels under all conditions after C showed similar behaviour to that after as P.The findings indicate that physical performance capacity, cardiocirculatory system, metabolism and hormones were not negatively influenced by C.     

Novel selective cannabinoid CB(1) receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

Aim:

To characterize the biological profiles of MJ08, a novel selective CB₁ receptor antagonist.

Methods:

Radioligand binding assays were performed using rat brain and spleen membrane preparations. CB₁ and CB₂ receptor redistribution and intracellular Ca²⁺ ([Ca²⁺]_i) assays were performed with IN CELL Analyzer. Inverse agonism was studied using intracellular cAMP assays, and in guinea-pig ileum and mouse vas deferens smooth muscle preparations. In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice.

Results:

In radioligand binding assay, MJ08 selectively antagonized CB₁ receptor (IC₅₀=99.9 nmol/L). In EGFP-CB₁_U2OS cells, its IC₅₀ value against CB₁ receptor activation was 30.23 nmol/L (SR141716A: 32.16 nmol/L). WIN 55,212-2 (1 μmol/L) increased [Ca²⁺]_i in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB₁ cells. MJ08 (10 nmol/L–10 μmol/L) blocked both the WIN 55,212-2-induced effects. Furthermore, MJ08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA₂=10.29±1.05). MJ08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle. MJ08 significantly increased the cAMP level in CHO-hCB₁ cells with an EC₅₀ value of 78.6 nmol/L, which was lower than the EC₅₀ value for SR141716A (159.2 nmol/L). Besides the more potent pharmacological effects of cannabinoid CB₁ receptor antagonism in DIO mice, such as reducing food intake, decreasing body weight, and ameliorating dyslipidemia, MJ08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo.

Conclusion:

MJ08 is a novel, potent and selective CB₁ receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB₁ receptors.     

ATP,a partial agonist for the P2Z receptor of human lymphocytes

1. Although extracellular adenosine 5′-triphosphate (ATP) is the natural ligand for the P2Z receptor of human lymphocytes it is less potent than 3′-O-(4-benzoylbenzoyl)-ATP (BzATP) in opening the associated ion channel, which conducts a range of permeants including Ba²⁺ and ethidium⁺. We have quantified the influx of ethidium⁺ into lymphocytes produced by BzATP, ATP, 2-methylthio-ATP (2MeSATP) and ATPγS, studied competition between ATP and BzATP and investigated the effects of KN-62, a new and potent inhibitor of the P2Z receptor.
2. BzATP and ATP stimulated ethidium⁺ influx with EC₅₀ values of 15.4±1.4 μM (n=5) and 85.6±8.8 μM (n=5), respectively. The maximal response to ATP was only 69.8±1.9% of that for BzATP. Hill analysis gave n_H of 3.17±0.24 (n=3) and 2.09±0.45 (n=4) for BzATP and ATP, suggesting greater positive cooperativity for BzATP than for ATP in opening the P2Z receptor-operated ion channel.
3. A rank order of agonist potency of BzATP>ATP=2MeSATP>ATPγS was observed for agonist-stimulated ethidium⁺ influx, while maximal influxes followed a rank order of BzATP>ATP>2MeSATP>ATPγS.
4. Preincubation with 30–50 μM oxidized ATP (ox-ATP), an irreversible P2Z inhibitor, reduced the maximal response but did not change the steepness of the Ba²⁺ influx-response curve produced by BzATP (n_H 3.2 and 2.9 for 30 and 50 μM ox-ATP, respectively (n=2)).
5. ATP (300–1000 μM) added simultaneously with 30 μM BzATP (EC₉₀) inhibited both ethidium⁺ and Ba²⁺ fluxes to a maximum of 30–40% relative to the values observed with BzATP alone. Moreover, ATP (300 μM) shifted the concentration-response curve to the right for BzATP-stimulated Ba²⁺ influx, confirming competition between ATP and BzATP.
6. KN-62, a new and powerful inhibitor of the lymphocyte P2Z receptor, showed less potency in antagonizing BzATP-mediated fluxes than ATP-induced fluxes when maximal concentrations of both agonists (BzATP, 50 μM; ATP, 500 μM) were used.
7. These data suggest that the natural ligand, ATP, is a partial agonist for the P2Z receptor while BzATP is a more efficacious agonist. Moreover the competitive studies show that only a single class of P2-receptor (P2Z class) is expressed on human leukaemic lymphocytes.

     

Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator

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Development of a selective S1P1 receptor agonist,Syl930, as a potential therapeutic agent for autoimmune encephalitis

Sphingosine-1-phosphate receptor subtype 1 (S1P₁) is essential for lymphocyte egress from secondary lymphoid organs and is a validated drug target for the treatment of autoimmune disorders. However, during the preclinical and clinical trials of S1P₁ modulators, the undesired activation of S1P₃, a subtype of sphingosine 1-phosphate (S1P) receptors family, by S1P₁ modulators often results in bradycardia in patients. Thus, we designed and synthesized a new series of selective S1P₁ agonists. One of them, Syl930 (the prodrug), is preference to activate S1P₁ but not S1P₃. In this study, we further investigated the therapeutic potential of Syl930 on an experimental autoimmune encephalomyelitis (EAE) model in Lewis rats. We found that Syl930 can activate and internalize S1P₁ receptors and effectively decreased the periphery blood lymphocytes (PBL) in SD rats, and subsequently rendered PBL insensitive to egress signal from secondary lymphoid organs (SLO). Intriguingly, the treatment of Syl930 did not bring any side effect on heart rate of the tested rats. Furthermore, the suppressed PBL caused by Syl930 was able to recover within 3 days after the last dose of treatment, which is correlated to the relatively short elimination half-life of Syl930. In the rat EAE model, therapeutic treatment with Syl930 significantly inhibited the progression of EAE and EAE-associated histological changes in brain and spinal cord of Lewis rats. These results illustrate that, as a selective S1P₁ agonist, Syl930 exhibits a profound and rapidly reversible suppression of lymphocyte trafficking and it has the potential to serve as a therapeutic agent for autoimmune encephalitis.     

Pharmacological profile of LY301317, a potent and selective 5-HT1A agonist

LY301317 ((4r)-(−)-4-(dipropylamino)-6-(5-oxazolinyl)-1,3,4,5-tetrahydrobenz[c,d]indole) has high affinity for the 5-HT_1A receptor and weak affinity for the 5-HT_1D and histamine-H₁ receptors. No significant affinity was found for the other amine receptors studied. In rats, LY301317 produced potent in vivo effects that are characteristic of compounds with agonist activity at the 5-HT_1A receptor, such as an increase in serum corticosterone concentration, a reduction in 5-HIAA concentration in brain tissue, induction of flat body posture and lower lip retraction (components of a serotonin syndrome), and a decrease of core body temperature. In pigeons trained to discriminate 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) from saline, full generalization to LY301317 was observed. LY301317 increased punished responding in both the pigeon and rat conflict tests for anxiolytic activity. LY301317 reduced immobility in the rat forced swim model used to indicate potential antidepressant activity. In pigeons, LY301317 blocked emesis induced by a chemical (ditolyguanidine), by a 5-HT₃ agonist (m-(chlorophenyl)-biguanide), and by an oncolytic agent (cisplatin), as well as vomiting induced by conditioning to environmental stimuli (a model of anticipatory nausea and vomiting). In addition, LY301317 blocked cisplatin- and ipecac-induced vomiting in the dog and motion-induced emesis in the cat. It was concluded that LY301317 is an orally active, potent, and selective agonist for the 5-HT_1A receptor with potential clinical utility as an anxiolytic, an antidepressant, and a broad-spectrum antiemetic. Drug Dev. Res. 40:17–34, 1997. © 1997 Wiley-Liss, Inc.     

Discovery of PIPE-359, a Brain-Penetrant,Selective M1 Receptor Antagonist with Robust Efficacy in Murine MOG-EAE

The discovery of PIPE-359, a brain-penetrant and selective antagonist of the muscarinic acetylcholine receptor subtype 1 is described. Starting from a literature-reported M₁ antagonist, linker replacement and structure–activity relationship investigations of the eastern 1-(pyridinyl)piperazine led to the identification of a novel, potent, and selective antagonist with good MDCKII-MDR1 permeability. Continued semi-iterative positional scanning facilitated improvements in the metabolic and hERG profiles, which ultimately delivered PIPE-359. This advanced drug candidate exhibited robust efficacy in mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE), a preclinical model for multiple sclerosis.