Ligand Design for Alpha1 Adrenoceptors

Bremner, John B.; Griffith, Renate; Çoban, Burak

doi:10.2174/0929867013373110

Cited by 20 publications

(10 citation statements)

References 41 publications

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“…In particular, the relative positions of the protonated nitrogen atom and the aromatic systems differ for quinazoline derivatives, raising the so-called 'prazosin problem'. From the obtained results, it is quite likely that the prazosin derivatives (which generally exhibit very high affinity for all three α 1 -AR subtypes, but little subtype selectivity) bind to a site that is different from that of other antagonists, and common to all α 1 -ARs [14,15].…”

Section: Design Of Prazosin Derivativesmentioning

confidence: 92%

Recent advances in the design and synthesis of prazosin derivatives

Minarini¹,

Bolognesi²,

Tumiatti³

et al. 2006

Expert Opinion on Drug Discovery

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Due to the large number of therapeutic indications, particularly for antagonists, a field of constant interest in medicinal chemistry is the design, synthesis and pharmacological evaluation of ligands that bind at α1-adrenoreceptors, which include α1a, α1b and α1d subtypes. This review, which is mainly based on literature over the past 10 years, focuses on the developments of some of the most potent, selective and widely used α1-adrenoreceptor antagonists that are structurally related to prazosin (which is characterised by a quinazoline moiety). Initially introduced in therapy for the management of hypertension, prazosin derivatives have become increasingly common in the treatment of benign prostatic hyperplasia. During the past few years, new perspectives have emerged for the use of these derivatives as a novel class of apoptosis-inducing agents in prostate cancer.

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Section: Design Of Prazosin Derivativesmentioning

confidence: 92%

Recent advances in the design and synthesis of prazosin derivatives

Minarini¹,

Bolognesi²,

Tumiatti³

et al. 2006

Expert Opinion on Drug Discovery

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“…[7,8] Barbaro et al used a series of pyridiazionone derivatives based on biological data from the rat receptor as a training set. [7] Their model resembles the class I pharmacophore described above in terms of pharmacophoric points and was shown to be well suited for a quantitative prediction of the biological activity of the training-set molecules and chemically closely related series.…”

Section: Description Of Gpcr Antitarget Pharmacophoresmentioning

confidence: 99%

“…The model generated by Bremner et al, on the other hand, was derived from a diverse set of 38 compounds. [8] However, it comprises only three pharmacophoric features and is thus quite generic and cannot be expected to be very selective.…”

Section: Description Of Gpcr Antitarget Pharmacophoresmentioning

confidence: 99%

GPCR Antitarget Modeling: Pharmacophore Models for Biogenic Amine Binding GPCRs to Avoid GPCR‐Mediated Side Effects

2005

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G protein-coupled receptors (GPCRs) form a large protein family that plays an important role in many physiological and pathophysiological processes. However, the central role that the biogenic amine binding GPCRs and their ligands play in cell signaling poses a risk in new drug candidates that reveal side affinities towards these receptor sites. These candidates have the potential to interfere with the physiological signaling processes and to cause undesired effects in preclinical or clinical studies. Here, we present 3D cross-chemotype pharmacophore models for three biogenic amine antitargets: the alpha(1A) adrenergic, the 5-HT(2A) serotonin, and the D2 dopamine receptors. These pharmacophores describe the key chemical features present within these biogenic amine antagonists and rationalize the biogenic amine side affinities found for numerous new drug candidates. First applications of the alpha(1A) adrenergic receptor model reveal that these in silico tools can be used to guide the chemical optimization towards development candidates with fewer alpha(1A)-mediated side effects (for example, orthostatic hypotension) and, thus, with an improved clinical safety profile.

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“…The α 1 -adrenergic receptors (α 1 -AR) fall into the family of G-protein coupled receptors (GCPR) and participate in the regulation of the cardiovascular system and smooth muscle contraction [1]. To date, there exists no known high-resolution 3D structure for any adrenergic receptor, however, an α 1 -pharmacophore proposed nineteen years ago has been successfully used for various sets of active substances [2].…”

Section: Introductionmentioning

confidence: 99%

The α 1-adrenolytic and structural evaluation of new pyridoindole derivatives

et al. 2006

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Abstractα1 — adrenolytic activities of pyridoindole derivatives recently synthesized in the Institute of Experimental Pharmacology, Slovak Academy of Sciences, were measured. A characteristic set of derivatives (five active, one with a threshold activity and two inactive) was chosen and an elementary structure-activity study was performed. The structure and energy properties were estimated by quantum-chemical semiempirical AM1 and molecular mechanics methods. The ionization constants pKα of the individual derivatives were calculated by program Pallas or estimated by potenciometric titration. The α 1 blocking activities were measured by rat thoracic aorta model. The experimental model used was not α 1 — adrenoreceptor subtypes specific, however, the α 1D subtype could be considered to be a predominant type in a rat aorta. The obtained physico-chemical parameters were then compared with the blocking activities of the derivatives and following determining characters for α 1 — adrenolytic activities were determined: 1) the polarity of the substituted phenol ring represented by a map of molecular electrostatic potential and 2) the hexahydro-pyridine nitrogen pKα constant, which represents the ability of the compound to be protonated by physiologic pH.

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Ligand Design for Alpha1 Adrenoceptors

Cited by 20 publications

References 41 publications

Recent advances in the design and synthesis of prazosin derivatives

Recent advances in the design and synthesis of prazosin derivatives

GPCR Antitarget Modeling: Pharmacophore Models for Biogenic Amine Binding GPCRs to Avoid GPCR‐Mediated Side Effects

The α 1-adrenolytic and structural evaluation of new pyridoindole derivatives

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