DuP 734
目录号 : GC61822
DuP 734 是一种 sigma 受体拮抗剂，DuP 734 是一种有效的选择性 sigma 和 5-HT2 受体配体，对 D2 受体的亲和力弱。DuP 734 具有抗精神病活性，而没有抗精神病剂常见的副作用。
Cas No.:135135-87-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
DuP 734 is a sigma receptor antagonist. DuP 734 is a selective and potent sigma and 5-HT2 receptor ligand with weak affinity for D2 receptors. DuP 734 may have antipsychotic activity without the liability of motor side effects typical of neuroleptics[1][2][3].
DuP 734 potently blocks mescaline-induced scratching (ED50=0.35 mg/kg, p.o.) and aggressive activity (ED50=1.9 mg/kg, p.o.) and is relatively much weaker as an apomorphine antagonist (ED50=12 mg/kg, p.o.)[1]. Administration of DuP 734 potently antagonizes the binding of [3H]DuP 734 and [3H](+)-SKF 10,047 to brain sigma receptors in vivo with ID50 values of 0.02 and 0.07 mg/kg (0.07 and 0.25µmol/kg), respectively[2]. Following intravenous dosing, the disposition of DuP 734 in mice, rats, beagle dogs and cynomolgus monkeys is characterized by high total body systemic plasma clearance (46 to 87 mL/min/kg) and large steady-state volume of distribution (3.6 to 6.8 L/kg). The terminal elimination half-life ranged from 50 to 83 min. The gastrointestinal absorption from an aqueous solution is very rapid in mice and rats with peak DuP 734 plasma concentrations attain within 5 and 20 min following administration, respectively. The peak plasma concentrations in dogs and monkeys are attained within 45 and 130 min, respectively. The absolute bioavailability in mice ranges from 29 to 46% at doses of 3.1 to 30.1 mg/kg. The bioavailability increases from 4 to 10% and from 14 to 72% when doses are increased from 12.5 to 50 mg/kg and 1 to 3 mg/kg of DuP 734 in rats and dogs, respectively. The bioavailability in monkeys is 30.5% at 9.3 mg/kg DuP 734 dose. The dose dependent pharmacokinetics of DuP 734 is observed within narrow dose ranges in all animal species investigated[3].
References:
[1]. L Cook, et al. DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'- Oxoethyl)piperidine HBr], a Potential Antipsychotic Agent: Preclinical Behavioral Effects. J Pharmacol Exp Ther. 1992 Dec;263(3):1159-66.
[2]. M Watanabe, et al. [3H]1-(cyclopropylmethyl)-4-(2-(4-fluorophenyl)-2-oxoethyl) Piperidine HBr (DuP 734). A Selective Ligand for Sigma Receptors in Mouse Brain in Vivo. J Pharmacol Exp Ther. 1993 Sep;266(3):1541-8.
[3]. R P Kapil, et al. Dose and Species Dependent Pharmacokinetics of a Novel Sigma Receptor Antagonist, DuP 734. Res Commun Mol Pathol Pharmacol. 1995 Apr;88(1):3-20.
| Cas No. | 135135-87-4 | SDF | |
| Canonical SMILES | FC1=CC=C(C(CC2CCN(CC3CC3)CC2)=O)C=C1.[H]Br | ||
| 分子式 | C17H23BrFNO | 分子量 | 356.27 |
| 溶解度 | DMSO : 250 mg/mL (701.71 mM) | 储存条件 | 4°C, stored under nitrogen, away from moisture |
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| 1 mM | 2.8069 mL | 14.0343 mL | 28.0686 mL |
| 5 mM | 0.5614 mL | 2.8069 mL | 5.6137 mL |
| 10 mM | 0.2807 mL | 1.4034 mL | 2.8069 mL |
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[3H]DuP 734 [1-(cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr]: a receptor binding profile of a high-affinity novel sigma receptor ligand in guinea pig brain
J Pharmacol Exp Ther 1992 Dec;263(3):1175-87.PMID:1361573doi
The in vitro binding properties of 1-(cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'-oxoethyl)pipe ridi ne HBr, [3H]DuP 734, a novel sigma receptor ligand, were examined in homogenates of guinea pig brain. Specific [3H]DuP 734 binding (10 microM haloperidol-displaceable) in cerebellum was dependent on pH, temperature and membrane protein concentration, reversible, saturable and of high affinity (KD = 228 +/- 34 pM; Bmax = 3856 +/- 340 fmol/mg protein). [3H]DuP 734 binding was substantially reduced by treating the membrane with proteases and completely abolished by heat denaturation. [3H]DuP 734 binding was unaffected by the presence of ions or guanine nucleotides. The pharmacological characteristics of [3H]DuP 734 binding in cerebellum displayed the same rank order and stereospecificity as previously reported for sigma receptors in brain. [3H]DuP 734-labeled sigma receptors were heterogeneously distributed throughout the central nervous systems with highest densities present in pons/medulla, hypothalamus, spinal cord and cerebellum. In addition to labeling sigma receptors, a second, lower affinity, haloperidol-insensitive [3H] DuP 734 binding site was observed in the cerebral cortex. This second site could not be positively identified as a neuronal receptor because a series of standard compounds were unable to displace [3H]DuP 734 from the haloperidol-insensitive site; only structural analogs of DuP 734 proved effective in displacing [3H]DuP 734 from the haloperidol-insensitive site. In summary, [3H]DuP 734 is a novel ligand that binds with high affinity to sigma receptors in brain.
DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)- piperidine HBr], a sigma and 5-hydroxytryptamine2 receptor antagonist: receptor-binding, electrophysiological and neuropharmacological profiles
J Pharmacol Exp Ther 1992 Dec;263(3):1167-74.PMID:1361572doi
It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs and that 5-hydroxytryptamine (5-HT2) receptor antagonists produce improvements of the negative symptoms of schizophrenia. [1-(Cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr] (DuP 734) is a novel compound with high affinity for the sigma (Ki = 10 nM) and 5-HT2 (Ki = 15 nM) receptors, but low affinity for dopamine receptors (Ki > 1000 nM) as well as 33 other receptors, ion channels and second messenger systems in vitro. DuP 734 did not inhibit the synaptosomal uptake of dopamine, 5-HT or norepinephrine. Oral administration of DuP 734 potently blocked 5-hydroxy-L-trytophan (5-HTP)-induced head twitch in the rat (ED50 = 6.5 mumol/kg), indicating 5-HT2 antagonist activity. Extracellular single-unit recording studies demonstrated that DuP 734 antagonized the effect of the selective sigma ligand (+)-3-(3-hydroxyphenyl-N-(1-propyl) piperidine [(+)-3-PPP] on dopamine neuronal activity in the substantia nigra of the rat with an ED90 of 3.6 mumol/kg i.v. The sigma receptor agonists (+)-SKF 10,047 and phencyclidine both elicited rotational behavior in rats with unilateral lesion of the substantia nigra. The rotational behavior induced by either (+)-SKF 10,047 or phencyclidine was dose-dependently antagonized by DuP 734 with oral ED50 of 8.7 and 19.6 mumol/kg, respectively. The 5-HT2 receptor antagonist ICI 169,369, even at high doses (up to 33 mumol/kg, s.c.), did not antagonize the rotational behavior induced by (+)-SKF 10,047.(ABSTRACT TRUNCATED AT 250 WORDS)
[3H]1-(cyclopropylmethyl)-4-(2-(4-fluorophenyl)-2-oxoethyl) piperidine HBr (DuP 734). A selective ligand for sigma receptors in mouse brain in vivo
J Pharmacol Exp Ther 1993 Sep;266(3):1541-8.PMID:8371156doi
1-(Cyclopropylmethyl)-4-(2-(4-fluorophenyl)-2-oxoethyl) piperidine HBr (DuP 734) is a novel sigma receptor ligand which exhibits promise in preclinical animal models as an antipsychotic agent without motor side effects. In vitro and in vivo receptor binding profiles of DuP 734 in mouse brain using [3H]DuP 734 and [3H]N-allylnormetazocine ((+)-SKF 10,047) were studied. The pharmacology and stereospecificity of [3H]DuP 734-labeled sites in mouse brain, both in vitro and in vivo, was consistent with sigma receptor pharmacology. Specific in vivo binding of [3H]DuP 734 in brain peaked 1 hr after i.v. injection and this level of binding was maintained up to 4 hr. On the other hand, plasma concentration of [3H]DuP 734 decreased rapidly within 20 min after injection, indicating different pharmacokinetics between brain and plasma levels. Nonspecific binding, defined using 1 mg/kg (2.66 mumol/kg) of haloperidol, was approximately 30% of total binding 1 hr after injection of radiotracer. Administration of DuP 734 potently antagonized the binding of [3H]DuP 734 and [3H](+)-SKF 10,047 to brain sigma receptors in vivo with ID50 values of 0.02 and 0.07 mg/kg (0.07 and 0.25 mumol/kg), respectively. However, (+)-SKF 10,047, which possess a high affinity (IC50 = 22.5 nM) for [3H]DuP 734 binding in vitro, failed to displace [3H]DuP 734 binding in vivo. Thus in vitro receptor binding data may not predict in vivo receptor occupancy. Overall, the data suggest [3H] DuP 734 is a good ligand for in vivo imaging of sigma receptors.
DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'- oxoethyl)piperidine HBr], a potential antipsychotic agent: preclinical behavioral effects
J Pharmacol Exp Ther 1992 Dec;263(3):1159-66.PMID:1361571doi
It has been suggested that sigma receptors may be involved in the etiology of psychosis and that 5-hydroxytryptamine2 (5-HT2) antagonists may have utility in treating the negative symptoms of psychosis as well as reducing the side effects associated with the typical antipsychotic haloperidol. We have evaluated the potential antipsychotic effects of 1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)piper i din e HBr (DuP 734), a selective and potent sigma and 5-HT2 receptor ligand with weak affinity for D2 receptors, in behavioral animal models that are not necessarily dependent on dopamine antagonism. DuP 734 potently blocked mescaline-induced scratching (ED50 = 0.35 mg/kg, p.o.) and aggressive activity (ED50 = 1.9 mg/kg, p.o.) and was relatively much weaker as an apomorphine antagonist (ED50 = 12 mg/kg, p.o.). This was in contrast to the typical antipsychotic agents such as haloperidol and chlorpromazine, which were very potent in all three tests. In rats, DuP 734 did not antagonize avoidance behavior or induce catalepsy, and, therefore, differed from the potent dopamine receptor antagonist antipsychotics. It did, however, reduce lever response rates in a random interval 60-sec food reward schedule of reinforcement (ED50 = 6.0 mg/kg, p.o.) in rats. The results suggest that DuP 734 may have antipsychotic activity without the liability of motor side effects typical of neuroleptics. Although DuP 734 itself did not antagonize avoidance activity, it significantly enhanced the potency of haloperidol in blocking avoidance behavior by 3-fold (by shifting the ED50 from 0.94 to 0.36 mg/kg, p.o.), whereas the ED50 of haloperidol for blockade of escape behavior and induction of catalepsy was not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Autoradiographic identification and characterization of sigma receptors in guinea pig brain using [3H]1(cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'-oxoethyl) piperidine ([3H]DuP 734), a novel sigma receptor ligand
Brain Res 1992 Dec 11;598(1-2):76-86.PMID:1486505DOI:10.1016/0006-8993(92)90170-e.
The psychotomimetic effects of certain cycloalkyls and benzomorphans that interact with sigma receptors has led to the hypothesis that these sites may be important in the etiology of schizophrenia. DuP 734 [1-(cyclopropylmethyl)-4-(2'-(4''-fluoro-phenyl)-2'-oxoethyl) piperidine HBr] is a novel sigma receptor ligand. The receptor binding specificity and neuroanatomical distribution of [3H]DuP 734-labeled sigma receptors in guinea pig brain were examined using quantitative autoradiography. [3H]DuP 734 binding (10 microM haloperidol displaceable) to slide-mounted sections of guinea pig brain was saturable and of high affinity (Ki = 3.9 nM). Competition studies, under conditions identical to those used to visualize the receptor, yielded the following rank order of potency: DuP 734 > haloperidol > (+)-pentazocine > (-)-butaclamol > DTG > (+)-SKF 10,047 > (+)-3-PPP > (-)-pentazocine > (+)-butaclamol > U50,488H > (-)-SKF 10,047 > cinanserin > PCP >> MK801, sulpiride. High densities of [3H]DuP 734 binding sites displaceable by haloperidol were present in the limbic system, in particular the dorsal and ventral bands of Broca as well as the ventral pallidum. Within the hippocampus, the pyramidal layers were sparsely labeled, while higher densities of binding sites were evident in the dentate gyrus. The frontal cortex, the mammillary complex of the hypothalamus, the central gray and red nucleus of the midbrain, the pontine reticular nucleus, the Purkinje cell layer of the cerebellum and dorsal and ventral horns, as well as the central gray matter of the spinal cord, all showed enrichments of [3H]DuP 734 binding sites. Lower levels of binding were present in the other regions of the cerebral cortex including parietal, pyriform, occipital, cingulate cortex, as well as the basal ganglia, and negligible specific binding was present in the white matter tracts. The kinetic and pharmacological characteristics and distribution of [3H]DuP 734 binding sites in brain are similar to those previously reported for sigma receptors.