Abstractα1‐adrenoceptor antagonists are widely used for hypertension (eg, doxazosin) and benign prostatic hypertrophy (BPH, eg, tamsulosin). Some antidepressants and antipsychotics have been reported to have α1 affinity. This study examined 101 clinical drugs and laboratory compounds to build a comprehensive understanding of α1‐adrenoceptor subtype affinity and selectivity. [3H]prazosin whole‐cell binding was conducted in CHO cells stably expressing either the full‐length human α1A, α1B, or α1D‐adrenoceptor. As expected, doxazosin was a high‐affinity nonselective α1‐antagonist although other compounds (eg, cyclazosin, 3‐MPPI, and ARC239) had higher affinities. Several highly α1A‐selective antagonists were confirmed (SNAP5089 had over 1700‐fold α1A selectivity). Despite all compounds demonstrating α1 affinity, only BMY7378 had α1D selectivity and no α1B‐selective compounds were identified. Phenoxybenzamine (used in pheochromocytoma) and dibenamine had two‐component‐binding inhibition curves at all three receptors. Incubation with sodium thiosulfate abolished the high‐affinity component suggesting this part is receptor mediated. Drugs used for hypertension and BPH had very similar α1A/α1B/α1D‐adrenoceptor pharmacological profiles. Selective serotonin reuptake inhibitors (antidepressants) had poor α1‐adrenoceptor affinity. Several tricyclic antidepressants (eg, amitriptyline) and antipsychotics (eg, chlorpromazine and risperidone) had high α1‐adrenoceptor affinities, similar to, or higher than, α blockers prescribed for hypertension and BPH, whereas others had poor α1 affinity (eg, protriptyline, sulpiride, amisulpiride, and olanzapine). The addition of α blockers for the management of hypertension or BPH in people already taking tricyclic antidepressants and certain antipsychotics may not be beneficial. Awareness of the α‐blocking potential of different antipsychotics may affect the choice of drug for those with delirium where additional hypotension (eg, in sepsis) may be detrimental.

01 Apr 1998·British Journal of PharmacologyQ2 · MEDICINE

α_1L‐Adrenoceptor mediation of smooth muscle contraction in rabbit bladder neck: a model for lower urinary tract tissues of man

Q2 · MEDICINE

Article

Author: Blue, David R. Jr. ; Vimont, Rachel L. ; Kava, M. Shannon ; Ford, Anthony P. D. W. ; Clarke, David E.

The α1‐adrenoceptor population mediating contractile responses to noradrenaline (NA) in smooth muscles of the bladder neck from rabbit (RBN) has been characterized by use of quantitative receptor pharmacology.

Experiments with several ‘key’ α1‐adrenoceptor antagonists of varying subtype selectivities (RS‐17053, BMY 7378, indoramin, 5‐methylurapidil, prazosin, REC 15/2739, SNAP 5089, terazosin, WB 4101, tamsulosin, (+)‐cyclazosin and RS‐100329) were conducted. Schild regression analyses yielded affinity (mean pKb) estimates of 7.1, 6.2, 8.6, 8.6, 8.4, 9.3, 7.0, 7.4, 8.9, 10.0, 7.1 and 9.3, respectively, although deviations from unit Schild regression slope question the robustness of data for RS‐17053 and SNAP 5089.

The nature of antagonism by these agents and the profile of affinity determinations generated together suggest that a single α1‐adrenoceptor subtype mediates contractile responses of RBN to NA. Additional studies with phenylephrine indicated also an agonist‐independence of this profile. Pharmacologically, this profile was reminiscent of that described as ‘α1L’ ‐adrenoceptor, which has been shown to mediate contractions of several tissues including lower urinary tract (LUT) tissues of man. Furthermore, a similarity was noticed between the ‘α1L’ ‐adrenoceptor described here in RBN and the rabbit and human cloned α1a‐adrenoceptor (based on data from both whole cell radioligand binding at 37°C and [3H]‐inositol phosphates accumulation assays), characterizations of which have been published elsewhere.

In conclusion, the RBN appears to provide a predictive pharmacological assay for the study of NA‐induced smooth muscle contraction in LUT tissues of man.

British Journal of Pharmacology (1998) 123, 1359–1366; doi:10.1038/sj.bjp.0701748

01 Feb 1997·British Journal of PharmacologyQ2 · MEDICINE

Pharmacological characterization of an α_1A‐adrenoceptor mediating contractile responses to noradrenaline in isolated caudal artery of rat

Q2 · MEDICINE

Article

Author: Ford, Anthony P. D. W. ; Lachnit, Wilhelm G. ; Clarke, David E. ; Tran, Antares M.

The α1‐adrenoceptor population mediating contraction of caudal artery of rat has been characterized by using quantitative receptor pharmacology.

Cumulative concentration‐effect (E/[A]) curves to noradrenaline (NA) yielded a p[A]50 of 5.56±0.05 (n=16). Prazosin caused concentration‐dependent, parallel, dextral shifts of E/[A] curves to NA yielding a pKb of 8.9 (Schild regression slope=1.0). RS‐17053 (N‐[2‐(2‐cyclopropyl methoxy phenoxy) ethyl]‐5‐chloro‐α,α‐dimethyl −1H‐indole‐ 3‐ethanamine hydrochloride; 10–100 nm), a selective α1A‐adrenoceptor antagonist, produced non‐parallel, biphasic, dextral shifts of E/[A] curves to NA, suggesting the involvement of more than one α1‐adrenoceptor subtype. Analysis of the high affinity component yielded an apparent pA2 value of 9.2±0.3.

A‐61603, a selective agonist at α1A adrenoceptors behaved as a full agonist relative to NA and yielded monophasic E/[A] curves with a p[A50] of 7.59±0.04 (n=15). Pretreatment of tissues with chloroethylclonidine (CEC; 100 μm for 20 min, followed by 40 min washout), which preferentially alkylates α1B‐ and α1D‐adrenoceptors, did not alter E/[A] curves to A‐61603. Prazosin (3–300 nm) caused concentration‐dependent, parallel, dextral shifts of E/[A] curves to A‐61603 yielding a pA2 estimate of 9.2±0.2.

Experiments with α1‐adrenoceptor antagonists of varying subtype selectivities (RS‐17053, SNAP 5089, tamsulosin, 5‐methylurapidil, BMY 7378, HV 723 and REC 15/2739) revealed parallel dextral shifts of E/[A] curves to A‐61603. Schild regression analyses yielded pA2 estimates of 9.2, 9.3, 11.2, 9.0, 6.3, 8.7 and 10.0 for RS‐17053, SNAP 5089, tamsulosin, 5‐methylurapidil, BMY 7378, HV 723 and REC 15/2739, respectively, although deviations from unit slope (possibly reflecting a secondary involvement of another α1‐adrenoceptor) hindered estimations of pKb for some antagonists. The antagonist affinity profile obtained reflects best that described for the α1A‐adrenoceptor.

In conclusion, caudal artery of rat contracts in response to NA via activation of at least two α1‐adrenoceptor subtypes. One of these subtypes displays the pharmacology of the α1A‐adrenoceptor, while the other remains to be defined. Use of the novel selective agonist, A‐61603, allows for limited pharmacological isolation of the α1A‐adrenoceptor permitting characterization of the properties of selective antagonists.

British Journal of Pharmacology (1997) 120, 819–826; doi:10.1038/sj.bjp.0700983

100 Deals associated with SNAP-5089

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Indication	Highest Phase	Country/Location	Organization	Date
Arrhythmias, Cardiac	Discovery	US	Lundbeck Research USA, Inc.	-
Hypertension	Discovery	US	Lundbeck Research USA, Inc.	-
Prostatic Hyperplasia	Discovery	US	Lundbeck Research USA, Inc.	-
Prostatic Hyperplasia	Discovery	US	Merck & Co., Inc.	-

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