Pharmacological characteristics of Ro 115–1240, a selective α<sub>1A/1L</sub>‐adrenoceptor partial agonist: a potential therapy for stress urinary incontinence

Blue, David R.; Daniels, Donald V.; Gever, Joel R.; Jett, Mary‐Frances; O-Yang, Counde; Tang, Hai Ming; Williams, Timothy J.; Ford, Anthony

doi:10.1111/j.1464-410x.2004.04577.x

Cited by 47 publications

(28 citation statements)

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“…Although most imidazolines have better selectivity for the ␣ 2 ARs, cirazoline is a notable exception as a strong partial agonist that has 10-to 30-fold selectivity for ␣ 1A ARs over other ␣ 1 AR subtypes and 100-fold over ␣ 2 AR subtypes, where it displays mild antagonist properties (Ruffolo and Waddell, 1982;Minneman et al, 1994). In addition to partial agonism, the imidazoline backbone is thought to decrease the ability of imidazolines to raise blood pressure, which is a common disadvantage to using phenethylamine-type agonists, such as phenylephrine (Blue et al, 2004). Imidazoline is a nitrogen-containing heterocycle derived from imidazole, which dissipates the charged nitrogen over the ring and can therefore cross the blood-brain barrier, unlike phenylephrine (Guo et al, 1991;Davies and Wellman, 1992).…”

Section: Discussionmentioning

confidence: 99%

Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity

Doze

Papay

Goldenstein

et al. 2011

Molecular Pharmacology

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The role of ␣ 1 -adrenergic receptors (␣ 1 ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. ␣ 1A AR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term ␣ 1A AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the ␣ 1A AR. CAM-␣ 1A AR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the ␣ 1A AR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-␣ 1A AR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the ␣ 1A AR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-␣ 1A AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-␣ 1A AR mice was 10% longer than that of WT mice. Our results suggest that long-term ␣ 1A AR stimulation improves synaptic plasticity, cognitive function, mood, and longevity. This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders.

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Section: Discussionmentioning

confidence: 99%

Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity

Doze

Papay

Goldenstein

et al. 2011

Molecular Pharmacology

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“…For this purpose, two a1-adrenoceptor agonists (NS-49 and Ro 115-1240) have been developed. However, these compounds are full agonists of the a1A-adrenoceptor or partial agonists of the a1A/L-adrenoceptor (Obika et al, 1995;Blue et al, 2004;Musselman et al, 2004). Thus, more selective or specific drugs against a1L-adrenoceptors may lead to improved uroselectivity.…”

Section: Perspectivementioning

confidence: 99%

Phenotype pharmacology of lower urinary tract α₁‐adrenoceptors

Nishimune

Yoshiki

Uwada

et al. 2012

British J Pharmacology

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Keywordsa1L-adrenoceptor; a1A-adrenoceptor; benign prostatic hyperplasia (BPH); stress urinary incontinence (SUI); lower urinary tract; phenotype pharmacology a1-Adrenoceptors are involved in numerous physiological functions, including micturition. However, the pharmacological profile of the a1-adrenoceptor subtypes remains controversial. Here, we review the literature regarding a1-adrenoceptors in the lower urinary tract from the standpoint of a1L phenotype pharmacology. Among three a1-adrenoceptor subtypes (a1A, a1B and a1D), a1a-adrenoceptor mRNA is the most abundantly transcribed in the prostate, urethra and bladder neck of many species, including humans. In prostate homogenates or membrane preparations, a1A-adrenoceptors with high affinity for prazosin have been detected as radioligand binding sites. Functional a1-adrenoceptors in the prostate, urethra and bladder neck have low affinity for prazosin, suggesting the presence of an atypical a1-adrenoceptor phenotype (designated as a1L). The a1L-adrenoceptor occurs as a distinct binding entity from the a1A-adrenoceptor in intact segments of variety of tissues including prostate. Both the a1L-and a1A-adrenoceptors are specifically absent from Adra1A (a1a) gene-knockout mice. Transfection of a1a-adrenoceptor cDNA predominantly expresses a1A-phenotype in several cultured cell lines. However, in CHO cells, such transfection expresses a1L-and a1A-phenotypes. Under intact cell conditions, the a1L-phenotype is predominant when co-expressed with the receptor interacting protein, CRELD1a. In summary, recent pharmacological studies reveal that two distinct a1-adrenoceptor phenotypes (a1A and a1L) originate from a single Adra1A (a1a-adrenoceptor) gene, but adrenergic contractions in the lower urinary tract are predominantly mediated via the a1L-adrenoceptor. From the standpoint of phenotype pharmacology, it is likely that phenotype-based subtypes such as the a1L-adrenoceptor will become new targets for drug development and pharmacotherapy. ---------------------------------------------------------------- LINKED ARTICLE IntroductionThe lower urinary tract is responsible for urine storage and voiding (Andersson and Wein, 2004). In mammalian species including humans, the bladder detrusor muscle contracts through a parasympathetic cholinergic mechanism during micturition (Abrams et al., 2006;Wess et al., 2007). Besides the importance of the cholinergic system as the major mechanism for bladder neck muscle tone control, the adrenergic systems play significant roles in the regulation of bladder neck tone (Fig. 1). During the storage phase, the urethra and outlet region of the bladder is contracted to Among impairments in urine storage, stress urinary incontinence (SUI) is recognized as one of the most frequently occurring conditions. Deficient urethral or bladder neck closure may result in this condition. However, drug treatments for SUI are scarce, at present (Andersson and Wein, 2004). The density of noradrenergic nerves increases markedly towards the bladder neck and ureth...

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“…Ro 115-1240 was originally developed as a partial α 1A -and α 1L -AR agonist (34). In our cell lines, however, Ro 115-1240 was in fact a partial agonist at α 1A -AR but was essentially inactive at the α 1L -AR.…”

Section: Discussionmentioning

confidence: 83%

“…Of note, recent studies have concluded that α 1L -AR is the functional α 1 -AR found in the lower urinary tract (14). Furthermore, α 1L -ARs in the lower urinary tract represent a new target for α 1 -AR antagonists for the treatment of urinary obstruction in men with benign prostatic hypertrophy (9,46) and for women with urinary incontinence (34,47). Thus, the α 1L -ARexpressing cell line should be of particular utility for the development of α 1L -AR-targeted drugs and for the pharmacological study of α 1L -ARs.…”

Section: Discussionmentioning

confidence: 99%

“…2a) and/or their intrinsic profile of two subtypes. Ro 115-1240, originally developed as a partial α 1A -and α 1L -AR agonist (34), showed agonist activity principally acting on the α 1A -AR. In contrast, MK017, a new α 1A -and α 1L -AR agonist (I. Muramatsu, unpublished observations), showed a higher potency than noradrenaline for both α 1 -AR subtypes.…”

Section: Agonist Pharmacology In α 1a -Ckd(α 1a -Enhanced) and α 1a -mentioning

confidence: 99%

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Identification of Cysteine-Rich Epidermal Growth Factor–Like Domain 1α (CRELD1α) as a Novel α1A-Adrenoceptor–Down-Regulating Protein and Establishment of an α1L-Adrenoceptor–Expressing Cell Line

et al. 2010

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Abstract. Two distinct α 1 -adrenoceptor phenotypes ( α 1A -and α 1L -ARs) are known to originate from a single ADRA1A( α 1a ) gene by an as-yet-unknown mechanism. We hypothesized that an α 1a -AR-interacting protein could generate the α 1L -AR phenotype and we sought to identify such a protein and to examine its effects on the expression of α 1A and α 1L phenotypes. Cysteine-rich epidermal growth factor-like domain 1 α (CRELD1 α ) was first identified using a yeast two-hybrid approach as an α 1a -AR-interacting protein. Transfection of α 1a -AR cDNA alone yielded Chinese hamster ovary (CHO) cells expressing α 1A -ARs having a predominant high affinity site for prazosin, with a low proportion (<10%) of prazosin-low affinity sites ( α 1L -AR). Knockdown of endogenous CHO-CRELD1 α [ α 1a -CKD( α 1A -enhanced) cells] enhanced the expression of α 1A -AR, whereas over-expression of CRELD1 α reduced α 1A -AR expression, yielding α 1a -COE( α 1L -dominant) cells expressing a high proportion (50%) of the α 1L -AR phenotype. The ligand binding and functional agonist and antagonist profiles in α 1a -CKD( α 1A -enhanced) and α 1a -COE( α 1L -dominant) cell lines were entirely in accord with the α 1A -AR and α 1L -AR phenotypes observed in intact tissues. CRELD1 α down-regulates expression of the α 1A -AR, thereby enhancing the proportion of expression of the α 1L -AR phenotype. The α 1L -AR-expressing α 1a -COE( α 1L -dominant) cell line reflects accurately the phenotype of this AR observed in vivo and will facilitate development of α 1L -AR-targeted drugs.

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Pharmacological characteristics of Ro 115–1240, a selective α_1A/1L‐adrenoceptor partial agonist: a potential therapy for stress urinary incontinence

Cited by 47 publications

References 30 publications

Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity

Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity

Phenotype pharmacology of lower urinary tract α₁‐adrenoceptors

Identification of Cysteine-Rich Epidermal Growth Factor–Like Domain 1α (CRELD1α) as a Novel α1A-Adrenoceptor–Down-Regulating Protein and Establishment of an α1L-Adrenoceptor–Expressing Cell Line

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Pharmacological characteristics of Ro 115–1240, a selective α1A/1L‐adrenoceptor partial agonist: a potential therapy for stress urinary incontinence

Cited by 47 publications

References 30 publications

Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity

Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity

Phenotype pharmacology of lower urinary tract α1‐adrenoceptors

Identification of Cysteine-Rich Epidermal Growth Factor–Like Domain 1α (CRELD1α) as a Novel α1A-Adrenoceptor–Down-Regulating Protein and Establishment of an α1L-Adrenoceptor–Expressing Cell Line

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Pharmacological characteristics of Ro 115–1240, a selective α_1A/1L‐adrenoceptor partial agonist: a potential therapy for stress urinary incontinence

Phenotype pharmacology of lower urinary tract α₁‐adrenoceptors