α-1 adrenoceptor

Upidocin is one of the drugs that works best on the prostate when compared to the apparent pKB value; yet, its potency is higher than that of 5-methylurapidide Er, prazosin, and terazosin, and slightly lower than that of tamsulosin[2]. Upidosin has binding affinity with pKi values of 9.0, 7.5, and 8.6 for human α1A, human α1B, and human α1D cloned adrenergic receptors, respectively [3].

In dogs under anesthesia, upidosin demonstrates greater selectivity compared to terazosin and tamsulosin, the other α-1 AR antagonists [1]. Upidocin (1-300 μg/kg; intravenously) has a pA2 value of 8.74, which is a more potent antagonist of phenylephrine-mediated rise of prostatic pressure than blood pressure, which has a pA2 value of 7.51 [3].

Alpha adrenoceptor antagonists have been convincingly shown to be beneficial in reducing both subjective and objective indices of urethral obstruction in benign prostatic hyperplasia. Rec 15/2739 (SB 216469) is a novel alpha-1 adrenoceptor (alpha-1 AR) antagonist currently being developed for benign prostatic hyperplasia. When evaluated in radioligand binding assays with expressed animal or human alpha-1 ARs, Rec 15/2739 shows marked to moderate selectivity for the alpha-1a AR subtype. Its affinity for the recombinant alpha-2 AR subtypes or native dopaminergic D2 receptor was about 100-fold lower than that for alpha-1a AR subtype. In canine tissues, Rec 15/2739 was 20-fold more potent as an inhibitor of [3H]prazosin binding to prostate vis-a-vis aorta. Functional studies in isolated rabbit tissues also confirmed the uroselectivity of Rec 15/2739, with substantially higher affinity (Kb = 2-3 nM) being observed in urethra and prostate, compared with ear artery and aorta (Kb = 20-100 nM). [1]

The aim of this study was to compare with known reference standards the functional in vitro alpha-1 antagonistic activity of Rec 15/2739 on noradrenaline-induced contractions of human prostate and mesenteric artery. We also characterized these tissues with regard to the alpha-1 adrenoceptor subtypes present. Comparing the apparent pKB values revealed Rec 15/2739 to be one of the most potent compounds action on the prostate. Its potency was slightly lower than that of tamsulosin and was higher than the potencies of prazosin, terazosin and 5-methylurapidil. On the mesenteric artery, tamsulosin was the most potent compound. Comparing the results from the functional studies with those obtained from radioreceptor binding studies, we found that the potency (pKB value) in inhibiting the contraction of prostatic tissue showed a close and significant correlation with the affinity for native and recombinant alpha-1A adrenoceptors. No significant correlation was found with affinity for either the native or the recombinant alpha-1B adrenoceptor subtype, or for recombinant alpha-1d receptors. Similar results were obtained for mesenteric artery. In order to characterize further the alpha-1 adrenoceptor subtypes present in the examined tissues, we investigated the functional effects of chloroethylclonidine, an alpha-1B-D subtypes selective alpha-1 adrenoceptor irreversible antagonist, and those of nifedipine, which antagonizes the extracellular calcium influx primarily mediated by alpha-1A adrenoceptor stimulation. The results indicate the presence of both chloroethylclonidine-sensitive and -insensitive alpha-1 adrenoceptor subtypes in the human prostate, whereas in mesenteric artery the alpha-1A subtype seems to be present exclusively. The possibility that the functionally relevant alpha-1 adrenoceptor subtype could be classified as alpha-1L in both tissues shoul also be considered. [2]

The in vitro selectivity observed with Rec 15/2739 was confirmed in vivo in the anesthetized dog, comparing potency against norepinephrine- or hypogastric nerve stimulation-induced urethral contraction with its ability to reduce diastolic blood pressure. In this model, Rec 15/2739 had greater selectivity than any other alpha-1 AR antagonist examined, including terazosin and tamsulosin. Based on the low potency of prazosin and some of its structural analogs in the rabbit and dog lower urinary tract tissues, it appears that norepinephrine contracts these tissues via activation of the alpha-1L AR. Hence this alpha-1 AR subtype, rather than the alpha-1A AR, may mediate the contraction in vivo. [1]

[1]. Leonardi A, et al. Pharmacological characterization of the uroselective alpha-1 antagonist Rec 15/2739 (SB 216469): role of the alpha-1L adrenoceptor in tissue selectivity, part I. J Pharmacol Exp Ther. 1997 Jun;281(3):1272-83.
[2]. Testa R, et al. Functional antagonistic activity of Rec 15/2739, a novel alpha-1 antagonist selective for the lower urinary tract, on noradrenaline-induced contraction of human prostate and mesenteric artery. J Pharmacol Exp Ther. 1996 Jun;277(3):1237-46.
[3]. Kenny BA, et al. Evaluation of the pharmacological selectivity profile of alpha 1 adrenoceptor antagonists at prostatic alpha 1 adrenoceptors: binding, functional and in vivo studies. Br J Pharmacol. 1996 Jun;118(4):871-8.

1. This study determined the in vitro antagonistic effects of a series of α1-adrenergic receptor antagonists on cloned human α1A, α1B, and α1D adrenergic receptors, as well as norepinephrine-mediated rat aortic and human prostate contractions. The in vivo effects of these compounds were determined in an anesthetized canine model, which simultaneously assessed the efficacy of the antagonists on phenylephrine-mediated increases in blood pressure and prostate pressure. 2. The quinazoline antagonists prazosin, doxazosin, and alfuzosin showed high affinity for all three clones of human α1-adrenergic receptors, but no selectivity. Indopramine and SNAP 1069 showed higher selectivity for α1A and α1B adrenergic receptors than for the α1D subtype. Rec 15/2739, WB 4101, SL 89,0591, (+)-, and (-)-tamsulosin showed selectivity for α1A and α1D adrenergic receptors relative to the α1B subtype. RS 17053 exhibits high affinity and selectivity for the α1A adrenergic receptor (pKi 8.6) relative to the α1B (pKi = 7.3) and α1D (pKi = 7.1) isoforms. 3. (+)-tamsulosin, (-)-tamsulosin, SL 89,0591, Rec 15/2739, SNAP 1069, and RS 17053 appear to act as competitive antagonists of norepinephrine-mediated rat aortic contraction, producing pA2 affinity estimates similar to those of cloned human α1D adrenergic receptors. The resulting order is as follows: Prazosin = (-)-tamsulosin > Doxazosin > SL 89,0591 = (+)-tamsulosin > Rec 15/2739 > RS 17053 = SNAP 1069. 4. (-)-Tamsulosin is a very potent and insurmountable norepinephrine-mediated human prostate contraction antagonist with a pA2 value of approximately 9.8 at a 1 nM concentration. The corresponding (+)-enantiomer is 30 times less potent. The pA2 values of SL 89,0591, SNAP 1069, and Rec 15/2739 are comparable to their α1A receptor binding affinity. Prazosin's estimated affinity for the human prostate was lower than the corresponding binding affinity measured on α1A adrenergic receptors, while RS 17053 showed very weak antagonism towards the human prostate (pA2 = 6.0), compared to a high affinity measured on cloned human α1A adrenergic receptors (pKi = 8.6). In anesthetized dogs, in vivo pseudopA2 values showed that doxazosin, (+)-, and (-)-tamsulosin had similar affinities for norepinephrine-induced prostate and blood pressure elevation, suggesting that these drugs had little selectivity for prostate response in this model. SL 89,0591, and SNAP 1069 showed moderate selectivity for prostate pressure relative to blood pressure (3-fold and 6-fold, respectively). Rec 15/2739 is a more potent antagonist of norepinephrine-mediated prostate pressure elevation (“pA2” = 8.74), unlike the antagonist of blood pressure (“pA2” = 7.51). 6. The data from this study suggest that the α1-adrenergic receptors mediating norepinephrine-induced human prostate contraction, while possessing some characteristics of the α1A adrenergic receptor, are not satisfactorily consistent with clonal α1A, α1B, or α1D adrenergic receptors. Furthermore, studies in anesthetized dogs have shown that drugs with high affinity and selectivity for prostate α1-adrenergic receptors (especially the α1D subtype) appear to selectively inhibit norepinephrine-induced prostate pressure elevation compared to blood pressure. [3]

C31H33N3O4

511.622

511.247

C, 72.78; H, 6.50; N, 8.21; O, 12.51

152735-23-4

152735-24-5 (mesylate); 171894-73-8 (mesylate monohydrate); 152735-23-4;

148842

White to off-white solid powder

1.208g/cm3

688.9ºC at 760 mmHg

370.4ºC

7.91E-19mmHg at 25°C

1.608

5.296

1

6

8

38

846

0

COC1C=CC=CC=1N1CCN(CCCNC(C2C3=C(C(=O)C(C)=C(C4C=CC=CC=4)O3)C=CC=2)=O)CC1

DUCNHKDCVVSJLG-UHFFFAOYSA-N

InChI=1S/C31H33N3O4/c1-22-28(35)24-12-8-13-25(30(24)38-29(22)23-10-4-3-5-11-23)31(36)32-16-9-17-33-18-20-34(21-19-33)26-14-6-7-15-27(26)37-2/h3-8,10-15H,9,16-21H2,1-2H3,(H,32,36)

N-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]-3-methyl-4-oxo-2-phenylchromene-8-carboxamide

Upidosin; SB 216469-S; UPIDOSIN; 152735-23-4; Rec 15-2739; Upidosin [INN]; TXG28R7G4Y; N-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]-3-methyl-4-oxo-2-phenylchromene-8-carboxamide; CHEMBL278865; 4H-1-Benzopyran-8-carboxamide, N-(3-(4-(2-methoxyphenyl)-1-piperazinyl)propyl)-3-methyl-4-oxo-2-phenyl-; Rec-15-2739

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~250 mg/mL (~488.65 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)