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Dive into the research topics where Timothy J. Williams is active.

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Featured researches published by Timothy J. Williams.


British Journal of Pharmacology | 1999

In vitroα1‐adrenoceptor pharmacology of Ro 70–0004 and RS‐100329, novel α1A‐adrenoceptor selective antagonists

Timothy J. Williams; David R. Blue; Donald V. Daniels; B Davis; T Elworthy; Joel R Gever; M S Kava; D Morgans; Fernando Padilla; S Tassa; Rachel L. Vimont; Christopher R. Chapple; Russell Chess-Williams; Richard M. Eglen; D E Clarke; Anthony P. D. W. Ford

It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the α1A‐adrenoceptor‐mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. The present study describes the α1‐adrenoceptor (α1‐AR) subtype selectivities of two novel α1‐AR antagonists, Ro 70‐0004 (aka RS‐100975) and a structurally‐related compound RS‐100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second‐messenger studies in intact CHO‐K1 cells expressing human cloned α1A‐, α1B‐ and α1D‐AR showed nanomolar affinity and significant α1A‐AR subtype selectivity for both Ro 70‐0004 (pKi 8.9: 60 and 50 fold selectivity) and RS‐100329 (pKi 9.6: 126 and 50 fold selectivity) over the α1B‐ and α1D‐AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. Noradrenaline‐induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70‐0004 (pA2 8.8 and 8.9), RS‐100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing α1‐AR‐mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70‐0004 and RS‐100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). The α1A‐AR subtype selectivity of Ro 70‐0004 and RS‐100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a ‘uroselective’ agent for the treatment of symptoms associated with benign prostatic hyperplasia.


British Journal of Pharmacology | 1995

Functional evidence equating the pharmacologically‐defined α1A‐ and cloned α1C‐adrenoceptor: studies in the isolated perfused kidney of rat

David R. Blue; D.W. Bonhaus; Anthony P. D. W. Ford; J.R. Pfister; N.A. Sharif; I.A. Shieh; Rachel L. Vimont; Timothy J. Williams; David E. Clarke

1 The present study characterizes and classifies α1‐adrenoceptor‐mediated vasoconstriction in the isolated perfused kidney of rat using quantitative receptor pharmacology and compares the results to radioligand binding studies (made in clonedαl‐adrenoceptor subtypes, nativeα1A‐adrenoceptors in submaxillary gland of rat, andα1A‐adrenoceptors in several other tissues of rat). 2 Concentration‐effect curves to noradrenaline in the presence of 5‐methyl‐urapidil were biphasic, indicating αl‐adrenoceptor heterogeneity. Theαl‐adrenoceptor subtype mediating the first phase (low affinity for 5‐methyl‐urapidil) could not be ‘isolated’ for detailed pharmacological characterization but was defined by a sensitivity to inhibition by chloroethylclonidine and an inability of methoxamine to activate the site. Additionally, vasoconstriction mediated by thisα1‐adrenoceptor subtype or subtypes was abolished by nitrendipine (1 μm), thereby allowing characterization of the second, high affinity site for 5‐methyl‐urapidil. 3 The following antagonists interacted competitively with noradrenaline at theα?l‐adrenoceptor for which 5‐methyl‐urapidil exhibits high affinity (pKB value): WB 4101 (10.3)>prazosin (9.5) ∼ HV 723 (9.3) ∼ 5‐methyl‐urapidil (9.2)> phentolamine (8.6)> spiperone (pA2 = 8.1) ∼ toxymetazoline (7.9). In contrast, insurmountable antagonism was seen with S(+)‐ and R(−)−niguldipine, the S(+)‐isomer being approximately 30 fold more potent than the R(−)−isomer. Receptor protection experiments indicated that S(+)‐niguldipine interacted directly withα1‐adrenoceptors. Dehydroniguldipine acted as a competitive antagonist (pKB = 9.0). Thus, the results with antagonists define theα1‐adrenoceptor as anα1A‐adrenoceptor. 4 An agonist ‘fingerprint’ was constructed in the presence of nitrendipine to define further theα1A‐adrenoceptor. The following order and relativity of agonist potency was obtained: cirazoline (1) ∼ adrenaline (2)> noradrenaline (5)> phenylephrine (23) ∼ amidephrine (31)> methoxamine (71)>> isoprenaline (1456) ∼ dopamine (2210). 5 A high correlative association was shown between the affinity of antagonists obtained functionally in the isolated perfused kidney of rat and pKi values obtained from binding experiments with the cloned bovineαlC‐adrenoceptor (R2 = 0.85), nativeαlA‐adrenoceptors in submaxillary gland of rat (R2 = 0.79), andα1A‐adrenoceptors from several other tissues of rat (values taken from the literature, R2 = 0.89). 6 The present study demonstrates that theα1A‐adrenoceptor is the predominant α‐adrenoceptor subtype mediating vasoconstrictor responses to exogenously administered noradrenaline in the isolated perfused kidney of rat. More importantly, α1A‐adrenoceptors mediating vasoconstrictor responses to noradrenaline exhibited a pharmacological equivalency to the cloned bovineα1C‐adrenoceptor. Thus, definitive functional pharmacological data are provided for equating the two receptors and support results derived recently from molecular and radioligand binding studies.


British Journal of Pharmacology | 2001

The role of α1-adrenoceptors and 5-HT1A receptors in the control of the micturition reflex in male anaesthetized rats

Rachel K Conley; Timothy J. Williams; Anthony P. D. W. Ford; Andrew G. Ramage

The effects of the α1‐adrenoceptor antagonists doxazosin (0.1 – 2 mg kg−1), RS‐100329 (α1A; 0.01 – 1 mg kg−1), RS‐513815 (Ro 151‐3815, α1B; 0.3 – 3 mg kg−1) and BMY 7378 (α1D; 0.1 – 1 mg kg−1), the 5‐HT1A receptor agonist, 8‐OH‐DPAT (0.03 – 0.3 mg kg−1) and antagonist WAY‐100635 (0.03 – 0.3 mg kg−1) were investigated (i.v.) on the ‘micturition reflex’ in the urethane anaesthetized male rat. Reflex‐evoked urethra contractions were most sensitive to the inhibitory action of RS‐100329, followed by doxazosin, BMY 7378 and WAY‐100635 and then RS‐513815. The maximum inhibition was 66, 63, 54, 46 and 22% at doses of 0.3, 0.5, 0.3, 0.3 and 3 mg kg−1 respectively. BMY 7378 and 8‐OH‐DPAT decreased, while WAY‐100635 increased, the pressure threshold to induce bladder contraction. WAY‐100635 (0.01 mg kg−1) blocked the effects of BMY 7378 (1 mg kg−1) on bladder pressure and volume threshold. Doxazosin, RS‐100329 and BMY 7378 had a similar potency in inducing a fall in arterial blood pressure while WAY‐100635 only caused a fall at the highest dose. Therefore, reflex‐evoked urethral contraction involves the activation of α1A/1D‐adrenoceptors, as BMY 7378 and RS‐100329 are similarly potent in attenuating this effect. The ability of WAY‐100635 to attenuate this contraction may suggest that 5‐HT1A receptors are also involved. However, as this inhibition occurred at the highest dose of WAY‐100635, which also caused a fall in arterial blood pressure; this effect is considered to be due to blockade of α1‐adrenoceptors not 5‐HT1A receptors. Nevertheless the initiation of the ‘micturition reflex’ involves the activation of 5‐HT1A receptors.


BJUI | 2004

Pharmacological characteristics of Ro 115-1240, a selective alpha1A/1L-adrenoceptor partial agonist: a potential therapy for stress urinary incontinence.

David R. Blue; Donald V. Daniels; Joel R Gever; Mary-Frances Jett; Counde O'yang; H.M. Tang; Timothy J. Williams; Anthony P. D. W. Ford

To describe the preclinical pharmacology of Ro 115–1240, a peripherally acting selective α1A/1L‐adrenoceptor (AR) partial agonist, compared with the α1A/1L‐AR full agonist amidephrine, as AR agonists have some utility in the treatment of stress urinary incontinence (SUI) but are limited by undesirable cardiovascular and central nervous system side‐effects.


Advances in pharmacology | 1997

α1-Adrenoceptor Subtypes in the Human Carondiovascular and Urogenital Systems

Martin C. Michel; Katsunari Taguchi; Rafael Schäfers; Timothy J. Williams; David E. Clarke; Anthony P. D. W. Ford

Publisher Summary α 1 -adrenoceptors are most important in the human cardiovascular system in the vasulature. The subtype(s) mediating vasoconstriction in humans have not yet been firmly identified, but the radioreceptor assay appears to be a promising approach. Three subtypes of α 1 -adrenoceptors have been defined in pharmacological and molecular terms and are designated α 1A , α 1B , and α 1D . However, some data are not fully explained by these classifications, indicating the possible existence of additional subtypes. In particular, the low apparent affinity of prazosin in some functional assays has led to the proposal of an α 1 -adrenoceptor subtype with low prazosin affinity, which has been designated α 1 . This article focuses on radioligand binding and functional data of the three α 1 -adrenoceptor subtypes. α 1 -Adrenoceptors mediate numerous effects in the cardiovascular and urogenital systems. In the human lower urinary tract, α 1 -adrenoceptors mediate smooth-muscle contraction of bladder neck, urethra, and prostate. In the human prostate, the α 1A -adrenoceptor dominates at the protein level and probably is also most important for contraction. Low apparent affinities of some antagonists in functional tests with human prostate do not necessarily contradict the α 1A -adrenoceptor hypothesis but may relate to assay conditions.


Bioorganic & Medicinal Chemistry Letters | 2003

Synthesis, pharmacology and pharmacokinetics of 3-(4-Aryl-piperazin-1-ylalkyl)-uracils as uroselective α1A-antagonists

Francisco J. Lopez; L. Arias; R. Chan; D.E. Clarke; Todd R. Elworthy; Anthony P. D. W. Ford; A. Guzman; Saul Jaime-Figueroa; Jeffrey R. Jasper; David J. Morgans; Fernando Padilla; A. Perez-Medrano; C. Quintero; M. Romero; L. Sandoval; S.A. Smith; Timothy J. Williams; David R. Blue

Predominance in the urethra and prostate of the alpha(1A)-adrenoceptor subtype, which is believed to be the receptor mediating noradrenaline induced smooth muscle contraction in these tissues, led to the preparation of alpha(1A)-selective antagonists to be tested as uroselective compounds for the treatment of benign prostatic hyperplasia. Thus, a number of selective alpha(1A)-adrenoceptor antagonists were synthesized and assayed in vitro for potency and selectivity. Dog pharmacokinetic parameters of 12 (RO700004) and its metabolite 40 (RO1104253) were established. The relative selectivity of intravenously administered 12, 40 and standard prazosin to inhibit hypogastric nerve stimulation-induced increases in intraurethral prostatic pressure versus phenylephrine-induced increases in diastolic blood pressure in anesthetized dogs was 76, 71 and 0.6, respectively.


Trends in Pharmacological Sciences | 1994

α1-Adrenoceptor classification: sharpening Occam's razor

Anthony P. D. W. Ford; Timothy J. Williams; David R. Blue; David E. Clarke


European Journal of Pharmacology | 1999

Human cloned α1A-adrenoceptor isoforms display α1L-adrenoceptor pharmacology in functional studies

Donald V. Daniels; Joel R Gever; Jeffrey R. Jasper; M. Shannon Kava; John D. Lesnick; Trena D. Meloy; George Stepan; Timothy J. Williams; David E. Clarke; David J. Chang; Anthony P. D. W. Ford


Journal of Medicinal Chemistry | 1997

N-Arylpiperazinyl-N‘-propylamino Derivatives of Heteroaryl Amides as Functional Uroselective α1-Adrenoceptor Antagonists

Todd R. Elworthy; Anthony P. D. W. Ford; Gary W. Bantle; David J. Morgans; Rachel S. Ozer; Wylie Solang Palmer; David B. Repke; Magarita Romero; Leticia Sandoval; Eric Brian Sjogren; Francisco Xavier Talamas; Alfredo Vazquez; Helen Y. Wu; Nicolas F. Arredondo; David R. Blue; Andrea DeSousa; Lisa M. Gross; M. Shannon Kava; John D. Lesnick; Rachel L. Vimont; Timothy J. Williams; Quan-Ming Zhu; and Jürg R. Pfister; David E. Clarke


Archive | 2000

Oxazolone derivatives and uses thereof

David Llewellyn Coffen; Michael Patrick Dillon; Anthony P. D. W. Ford; Zhe Li; Timothy J. Williams

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