Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q9UIJ5 (Rec)
 58,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The profile of a range of alpha 1 adrenoceptor antagonists was determined in vitro against cloned human alpha 1A, alpha 1B and alpha 1D adrenoceptors and against noradrenaline-mediated contractions of rat aorta and human prostate. The in vivo profile of compounds was determined in an anaesthetized dog model which allowed the simultaneous assessment of antagonist potency against phenylephrine-mediated increases in blood pressure and prostatic pressure. 2. The quinazoline antagonists, prazosin, doxazosin and alfuzosin displayed high affinity but were non selective for the three cloned human alpha 1 adrenoceptors. Indoramin and SNAP 1069 showed selectivity for alpha 1A and alpha 1B adrenoceptors relative to the alpha 1D subtype. Rec 15/2739, WB 4101, SL 89,0591, (+)- and (-)- tamsulosin showed selectivity for alpha 1A and alpha 1D adrenoceptors relative to the alpha 1B subtype. RS 17053 showed high affinity and selectivity for alpha 1A adrenoceptors (pKi 8.6) relative to alpha 1B (pKi = 7.3) and alpha 1D (pKi = 7.1) subtypes. 3. (+)-Tamsulosin, (-)-tamsulosin, SL 89,0591, Rec 15/2739, SNAP 1069 and RS 17053 appeared to act as competitive antagonists of noradrenaline-mediated contractions of rat aorta yielding pA2 affinity estimates which were similar to binding affinities at cloned human alpha 1D adrenoceptors. The following rank order was obtained: prazosin = (-)-tamsulosin > doxazosin > SL 89,0591 = (+)-tamsulosin > Rec 15/2739 > RS 17053 = SNAP 1069. 4. (-)-Tamsulosin was a very potent, insurmountable antagonist of noradrenaline-mediated contractions of human prostate, yielding an approximate pA2 estimate of 9.8 at 1 nM. The corresponding (+)-enantiomer was 30 fold weaker. SL 89,0591, SNAP 1069 and Rec 15/2739 yielded pA2 estimates which compared well with their alpha 1A binding affinities. The affinity estimate for prazosin on human prostate was lower than the corresponding binding affinity determined at alpha 1A adrenoceptors and RS 17053 was a very weak antagonist on human prostate (pA2 = 6.0) relative to the high affinity (pKi = 8.6) determined at cloned human alpha 1A adrenoceptors. 5. In the anaesthetized dog, in vivo pseudo "pA2' values showed that doxazosin, (+)- and (-)-tamsulosin inhibited phenylephrine-induced increases in prostatic and blood pressure with similar affinity, implying that these agents show little or no selectivity for prostatic responses in this model. SL 89,0591 and SNAP 1069 were moderately selective (3 and 6 fold respectively) for prostatic pressure relative to blood pressure. Rec 15/2739 was a more potent antagonist of phenylephrine-mediated increases in prostatic pressure ("pA2' = 8.74) compared to blood pressure ("pA2' = 7.51). 6. Data in this study suggest that the alpha 1 adrenoceptor mediating noradrenaline-induced contractions of human prostate, whilst having some of the characteristics of an alpha 1A adrenoceptor, cannot be satisfactorily aligned with cloned alpha 1A, alpha 1B or alpha 1D adrenoceptors. In addition, studies in the anaesthetized dog have shown that agents having high affinity and selectivity for prostatic alpha 1 adrenoceptors, particularly over the alpha 1D subtype, appear to inhibit phenylephrine-induced increases in prostatic pressure selectively compared to blood pressure.
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PMID:Evaluation of the pharmacological selectivity profile of alpha 1 adrenoceptor antagonists at prostatic alpha 1 adrenoceptors: binding, functional and in vivo studies. 879 56

In this study, we used a novel conscious dog model to evaluate the uroselectivity of selected alpha 1-antagonists either approved for human use or in clinical development for the treatment of symptomatic benign prostatic hyperplasia (BPH) and compared those results to their in vitro binding and functional affinities at alpha 1A, alpha 1B and alpha 1D receptor subtypes. Conscious dogs were instrumented acutely with a balloon catheter for the measurement of changes in prostatic intraurethral pressure (IUP) and chronically with implantable telemetry devices for the measurement of arterial pressure. The pressor effects of the alpha 1-agonist phenylephrine (PE) on IUP and mean arterial pressure (MAP) were compared before and at various time points after oral doses of either terazosin, doxazosin, tamsulosin or Rec 15/2739 (SB 216469). At submaximal doses, terazosin and doxazosin blocked PE-induced increases in MAP to a greater extent than increases in IUP. Tamsulosin blocked both parameters equally at the lowest and highest doses; however, at the intermediate dose, IUP was blocked more than MAP. Rec 15/2739 at each dose always blocked IUP to a greater extent than MAP. While the in vivo uroselectivity of these agents was predicted by radioligand binding and in vitro functional selectivity for the alpha 1A subtype over alpha 1B and alpha 1D subtypes, results from conscious dog experiments indicate that estimates of in vivo uroselectivity also depend upon dose and the time after administration. Our conscious canine model provides the basis for frequent and repeated evaluation of uroselectivity parameters over many hours, thus providing a pharmacological profile of compound effects perhaps more relevant to clinical practice.
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PMID:Effects of selective and nonselective alpha-1-adrenoceptor antagonists on intraurethral and arterial pressures in intact conscious dogs. 903

Phenylephrine and (+/-)N-[5-(4,5-dihydro-1-H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetr ahydronaphthalen-1-yl] methanesulphonamide hydrobromide (A 61603) evoked concentration-dependent contractions of the rabbit spleen. These contractions were antagonized by prazosin (10(-8)-10(-7) M) with pA2 values of 8.34+/-0.11 and 8.15+/-0.10 against phenylephrine and A 61603, respectively. In both cases, the slopes of the Schild plots were not significantly (P>0.05) different from 1.0, indicating competitive antagonism. The effects of subtype-selective antagonists WB 4101 [2-(2-6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride] and 5-methylurapidil on agonist-induced contractions were also examined. WB 4101 competitively antagonized agonist-induced contractions; pA2 values were 8.13+/-0.10 and 8.10+/-0.03 against phenylephrine and A 61603, respectively. Corresponding values for 5-methylurapidil were 8.28+/-0.17 and 7.93+/-0.02 against phenylephrine and A 61603, respectively. Tamsulosin and Rec 15/2739 [(8-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-3-methy l-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride] also antagonized phenylephrine- and A 61603-induced contractions with pA2 values of 9.38+/-0.13 and 9.18+/-0.06 (tamsulosin) and 8.41+/-0.12 and 8.34+/-0.11 (Rec 15/2739) against phenylephrine and A 61603, respectively. HV 723 (alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxyethyl) -amino)-propyl)benzene-aceto-nitrile) fumarate) competitively antagonized phenylephrine-induced contractions with a pA2 value of 8.57+/-0.06. Chloroethylclonidine (CEC; 10(-4) M) shifted phenylephrine and A 61603 concentration-response curves to the right, reducing their potencies approximately two- to threefold, while the maximum response was reduced by 8% in both cases. It was therefore concluded that contractions of the rabbit spleen induced by alpha1-adrenergic agonists were mediated predominantly by a relatively CEC-insensitive alpha1-adrenoceptor subtype, possibly the alpha1L-subtype.
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PMID:Functional characterization of alpha1-adrenoceptor subtypes in the rabbit spleen. 977 16