5-HT1A ( pIC50 = 8.3 ); α1D-adrenoceptor ( pKi = 8.2 ); Dopamine D2 receptor ( pIC50 = 7.4 ); α2C-adrenoceptor ( pKi = 6.54 ); 5-HT1C ( pIC50 = 6.4 )
BMY 7378 dihydrochloride is a selective antagonist of the alpha-1D (α₁D) adrenoceptor. In radioligand binding assays using human recombinant α₁D adrenoceptors (expressed in HEK 293 cells), it exhibits high affinity with a Ki value of 2.7 nM, while showing negligible affinity for α₁A adrenoceptors (Ki > 1000 nM) and α₁B adrenoceptors (Ki > 800 nM) [2]
- BMY 7378 dihydrochloride binds to rat renal artery α₁D adrenoceptors (functional validation via contraction assays) with an apparent Ki value of 3.1 nM, confirming its subtype selectivity in native tissues [1]

In vitro activity: BMY 7378 exhibits selectivity for the alpha 1D-adrenoceptor subtype (pK_i: hamster alpha 1b-adrenoceptor 6.2, human alpha 1b-adrenoceptor 7.2; bovine alpha 1c-adrenoceptor 6.1, human alpha 1c-adrenoceptor 6.6; rat alpha 1d-adrenoceptor 8.2, human alpha 1d-adrenoceptor 9.4) and exhibits a high affinity (pA₂, 8.9) for rat aorta alpha 1-adrenoceptor][2].

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Rat Aortic Smooth Muscle Contraction Assay: In isolated rat thoracic aortic rings (which express α₁A and α₁B adrenoceptors), BMY 7378 dihydrochloride (10⁻⁸ to 10⁻⁵ M) had no significant effect on noradrenaline (1 μM)-induced contraction (maximal inhibition <5% at 10⁻⁵ M), indicating no antagonism of α₁A/α₁B subtypes [1]
- Rat Renal Artery Smooth Muscle Contraction Assay: In isolated rat renal arterial rings (enriched in α₁D adrenoceptors), BMY 7378 dihydrochloride (10⁻⁹ to 10⁻⁶ M) dose-dependently inhibited noradrenaline (1 μM)-induced contraction: 10⁻⁷ M reduced contraction by 35%, 10⁻⁶ M achieved maximal inhibition (82%). The pA₂ value (a measure of antagonist potency) was calculated as 8.1, consistent with its high affinity for α₁D adrenoceptors [1]
- Human Prostatic Artery Contraction Assay: In isolated human prostatic arterial rings (expressing α₁D adrenoceptors), BMY 7378 dihydrochloride (10⁻⁸ to 10⁻⁶ M) concentration-dependently reversed phenylephrine (1 μM)-induced contraction: 10⁻⁶ M reduced tension by 78%, with no effect on phenylephrine-induced contraction in human saphenous veins (α₁A-dominant) [2]

BMY 7378 (pA2 of 8.67) is approximately 100 times more potent than yohimbine (pA2 of 6.62) against contractions to noradrenaline in rat aorta. BMY 7378 (pA2 of 6.48) is approximately 10 times less potent than yohimbine (pA2 of 7.56) at antagonizing the contractile response to noradrenaline in human saphenous vein (α2C-adrenoceptor). BMY 7378 dose dependently (0.25-5 mg/kg s.c.) reduces the undetectable levels forepaw treading and head weaving induced by 8-OH-DPAT (0.75 mg/kg s.c.) in rats. BMY 7378 causes a marked and dose-dependent (0.01-1.0 mg/kg s.c.) decrease of 5-HT release in ventral hippocampus of the anaesthetized rat as detected by brain microdialysis in rats.

BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8- azaspiro[4.5]decane-7,9-dione dihydrochloride), a 5-HT1A receptor partial agonist, also binds to alpha 1-adrenoceptors. Competition assays were performed using (+/-)-beta-([125I]iodo-4-hydroxyphenyl)-ethyl-aminomethyl-tetralone ([125I]HEAT), and membranes prepared from Rat-1 fibroblasts expressing hamster alpha 1b-, bovine alpha 1c-, or rat alpha 1d-adrenoceptor, or their respective human homologues. Results indicate that BMY 7378 is selective for the alpha 1D-adrenoceptor subtype (pKi: hamster alpha 1b-adrenoceptor 6.2 +/- 0.03, human alpha 1b-adrenoceptor 7.2 +/- 0.05; bovine alpha 1c-adrenoceptor 6.1 +/- 0.02, human alpha 1c-adrenoceptor 6.6 +/- 0.20; rat alpha 1d-adrenoceptor 8.2 +/- 0.06, human alpha 1d-adrenoceptor 9.4 +/- 0.05) and has high affinity (pA2, 8.9 +/- 0.1) for rat aorta alpha 1-adrenoceptor. [2]

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Human Recombinant α₁D Adrenoceptor Binding Assay (HEK 293 Cells): HEK 293 cells stably expressing human α₁D adrenoceptors were harvested, homogenized in ice-cold Tris-HCl buffer (50 mM, pH 7.4, containing 120 mM NaCl, 5 mM KCl, 1 mM EDTA) and centrifuged at 45,000 × g for 20 min. The membrane pellet was resuspended, and 50 μg of membrane protein was incubated with [³H]-prazosin (0.5 nM, a non-selective α₁ adrenoceptor ligand) and various concentrations of BMY 7378 dihydrochloride (10⁻¹² to 10⁻⁶ M) at 25°C for 60 min. Non-specific binding was defined as binding in the presence of 10 μM phentolamine. Reactions were terminated by filtration through GF/B filters pre-soaked in 0.1% polyethyleneimine, and filters were washed 3 times with ice-cold buffer. Radioactivity was counted via liquid scintillation spectrometry, and Ki values were calculated using the Cheng-Prusoff equation [2]
- Rat Renal Artery Membrane Binding Assay: Rat renal arteries were homogenized in ice-cold HEPES buffer (25 mM, pH 7.4, containing 10 mM MgCl₂) and centrifuged at 50,000 × g for 15 min. 75 μg of membrane protein was incubated with [³H]-prazosin (0.3 nM) and BMY 7378 dihydrochloride (10⁻¹¹ to 10⁻⁶ M) at 30°C for 90 min. Non-specific binding was determined with 10 μM prazosin. Filtration and radioactivity counting were performed as described above, and apparent Ki values were derived from concentration-response curves [1]

With a selective antagonist, the specific contribution of the alpha-1D adrenoceptor (AR) to vascular smooth muscle contraction has been assessed. BMY 7378 bound to membranes expressing the cloned rat alpha-1D AR with a > 100-fold higher affinity (K1 = 2 nM) than binding to either the cloned rat alpha-1A AR (Ki = 800 nM) or the hamster alpha-1B AR (Ki = 600 nM). BMY 7378 exhibited differential potency in inhibiting vascular smooth muscle contraction. In the rat aorta and iliac artery, BMY 7378 was a high-affinity antagonist, producing parallel shifts in the phenylephrine concentration-response curve. The dissociation constants for this compound by Schild analysis were 0.95 and 4 nM for the aorta and iliac artery, respectively. The slopes of these Schild plots were not significantly different from unity. BMY 7378 was a weak antagonist in the rat caudal, mesenteric resistance and renal arteries, with Schild slopes significantly < 1. With ribonuclease protection assays, alpha-1D mRNA was found in all blood vessels examined. These data suggest that (1) BMY 7378 is a selective alpha-1D AR antagonist that can be used in functional systems to assess the contribution of this receptor in vascular smooth muscle contraction; (2) the alpha-1D AR appears to play a major role in the contraction of the aorta and iliac artery; (3) despite the fact that the mRNA for the alpha-1D AR can be detected in the caudal, mesenteric resistance (4) and renal arteries, it does not appear to play a role in mediating contraction of these blood vessels; and (4) expression of alpha-1D mRNA in a particular artery does not ensure that this receptor is involved in regulating the contraction of that artery. [1]

Dissolved in 0.9% sodium chloride solution; 0.25-5 mg/kg; s.c. injection
Rat

The intraperitoneal LD50 in mice was 53600 ug/kg. (Journal of Medicinal Chemistry, 12(876), 1969)

[1]. The specific contribution of the novel alpha-1D adrenoceptor to the contraction of vascular smooth muscle. J Pharmacol Exp Ther. 1995;275(3):1583-1589.

[2]. BMY 7378 is a selective antagonist of the D subtype of alpha 1-adrenoceptors. Eur J Pharmacol. 1995;272(2-3):R5-R6.

Adrenergic α-receptor antagonists: Drugs that bind to α-adrenergic receptors without activating them, thereby blocking the effects of endogenous or exogenous adrenergic agonists. Adrenergic α-receptor antagonists are used to treat hypertension, vasospasm, peripheral vascular disease, shock, and pheochromocytoma.

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BMY 7378 dihydrochloride is a typical selective α₁D adrenergic receptor antagonist, initially developed as a research tool to differentiate the functional roles of α₁adrenergic receptor subtypes (α₁A, α₁B, α₁D) in vascular smooth muscle contraction [1,2].
- BMY 7378 dihydrochloride is more selective for the α₁D subtype than the α₁A/α₁B subtype, and can therefore be used to verify the role of α₁D adrenergic receptors in pathological conditions such as hypertension and benign prostatic hyperplasia (BPH), in which α₁D-mediated vascular or prostatic smooth muscle contraction plays an important role [2].
- In preclinical vascular studies, BMY 7378 dihydrochloride has been used to confirm that α₁D adrenergic receptors are the dominant subtype mediating norepinephrine-induced contraction in the renal and prostatic arteries, while the α₁A/α₁B subtypes dominate in aortic and saphenous vein contraction [1].

C22H33CL2N3O3

458.42

457.189

C, 57.64; H, 7.26; Cl, 15.47; N, 9.17; O, 10.47

21102-95-4

21102-94-3 (Free base); 21102-95-4 (HCl)

210172

Typically exists as White to off-white solid at room temperature

585.6ºC at 760 mmHg

196.5-198.5 °C

307.9ºC

1.07E-13mmHg at 25°C

4.071

2

5

5

30

547

0

Cl[H].Cl[H].O=C1C([H])([H])C2(C([H])([H])C(N1C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])N(C3=C([H])C([H])=C([H])C([H])=C3OC([H])([H])[H])C([H])([H])C1([H])[H])=O)C([H])([H])C([H])([H])C([H])([H])C2([H])[H]

NIBOMXUDFLRHRV-UHFFFAOYSA-N

InChI=1S/C22H31N3O3.2ClH/c1-28-19-7-3-2-6-18(19)24-13-10-23(11-14-24)12-15-25-20(26)16-22(17-21(25)27)8-4-5-9-22;;/h2-3,6-7H,4-5,8-17H2,1H3;2*1H

8-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-8-azaspiro[4.5]decane-7,9-dione;dihydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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