Structure-Activity Relationships of Receptor Binding of 1,4-Dihydropyridine Derivatives

Takahashi, Daiki; Oyunzul, Luvsandorj; Onoue, Satomi; Ito, Yoshihiko; Uchida, Shinya; Şimşek, Rahime; Gündüz, Miyase Gözde; Şafak, Cihat; Yamada, Shizuo

doi:10.1248/bpb.31.473

Cited by 21 publications

(13 citation statements)

References 20 publications

(9 reference statements)

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“…In addition, the phenyl ring was replaced with different heteroatomic rings; some of these derivatives demonstrated modified tissue selectivity or the potency [30][31][32][33][34][35].…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

Ioan¹,

Carosati²,

Micucci³

et al. 2011

CMC

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Since the pioneering studies of Fleckenstein and co-workers, L-Type Calcium Channel (LTCC) blockers have attracted large interest due to their effectiveness in treating several cardiovascular diseases. Medicinal chemists achieved high potency and tissue selectivity by decorating the 1-4-DHP nucleus, the most studied scaffold among LTCC blockers. Nowadays it is clear that the 1,4-DHP nucleus is a privileged scaffold since, when appropriately substituted, it can selectively modulate diverse receptors, channels and enzymes. Therefore, the 1,4-DHP scaffold could be used to treat various diseases by a single-ligand multi-target approach. In this review, we describe the structure-activity relationships of 1,4-DHPs at ion channels, G-protein coupled receptors, and outline the potential for future therapeutic applications.

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“…In addition, the phenyl ring was replaced with different heteroatomic rings; some of these derivatives demonstrated modified tissue selectivity or the potency [30][31][32][33][34][35].…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

Ioan¹,

Carosati²,

Micucci³

et al. 2011

CMC

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“…An aryl group in the 4-position of the 1,4-DHP ring is essential for optimal activity (Shaldam et al, 2014). One study showed that an aryl ring with halogen or other electron-withdrawing groups exhibits higher receptorbinding activity (Takahashi et al, 2008). On the 1,4-DHP ring, ester groups are usually substituted at the 3-and 5-positions.…”

Section: Introductionmentioning

confidence: 99%

The effect of bromine scanning around the phenyl group of 4-phenylquinolone derivatives

Steiger

Monacelli

et al. 2014

Acta Crystallogr C

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Three quinolone compounds were synthesized and crystallized in an effort to study the structure-activity relationship of these calcium-channel antagonists. In all three quinolones, viz. ethyl 4-(4-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (I), ethyl 4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (II), and ethyl 4-(2-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (III), all C21H24BrNO3, common structural features such as a flat boat conformation of the 1,4-dihydropyridine (1,4-DHP) ring, an envelope conformation of the fused cyclohexanone ring and a bromophenyl ring at the pseudo-axial position and orthogonal to the 1,4-DHP ring are retained. However, due to the different packing interactions in each compound, halogen bonds are observed in (I) and (III). Compound (III) crystallizes with two molecules in the asymmetric unit. All of the prepared derivatives satisfy the basic structural requirements to possess moderate activity as calcium-channel antagonists.

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“…3 H]NMS in the rat brain homogenates were examined. Although the lower urinary tract is clinically important target of SPE, in this study, the brain tissue was used because of a similarity between brain and lower urinary tract of pharmacological agents and SPE in binding affinities of a 1 -adrenergic, muscarinic and 1,4-DHP receptors 10,20,21) and also because of less amount of nonspecific binding for each radioligand in the brain compared to the bladder and prostate. SPE (10-200 mg/ml) inhibited specific [ 3 H]prazosin binding in a concentration-dependent manner (Fig.…”

mentioning

confidence: 99%

Pharmacologically Relevant Receptor Binding Characteristics and 5.ALPHA.-Reductase Inhibitory Activity of Free Fatty Acids Contained in Saw Palmetto Extract

Abe

Ito

Oyunzul

et al. 2009

Biological & Pharmaceutical Bulletin

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Benign prostatic hyperplasia (BPH) and related lower urinary tract symptoms (LUTS) are common disorders in aging men. Plant extracts are widely used in the treatment of BPH and related LUTS. In fact, phytotherapeutic agents, including saw palmetto extract (SPE), are very popular in many European countries as herbal remedies, representing up to 80% of all drugs prescribed for these disorders.1,2) An analysis of many clinical trials showed mild to moderate improvements in symptom scores and urinary flow in patients with BPH.3)The most widely known effect of SPE is the inhibition of type 1 and 2 isozymes of 5a-reductase. 4,5) Other pharmacodynamic mechanisms of SPE have also been proposed, including anti-androgenic effects, anti-proliferative effects and anti-inflammatory effects. [6][7][8] Our recent study has shown that the intraduodenal administration of SPE in the rat cystometry resulted in a significant and dose-related increase in micturition interval as well as a decrease in micturition volume and bladder capacity caused by the infusion of 0.1% acetic acid.9) Furthermore, we have reported that SPE inhibited the specific binding of radioligands to a 1 -adrenergic, muscarinic and 1,4-dihydropyridine (1,4-DHP) calcium channel antagonist receptors in the lower urinary tract of rats.9-11) However, the exact active constituents of SPE remain to be identified. SPE contains mainly saturated and unsaturated fatty acids (90%). Among these fatty acids, the major constituents are oleic acid and lauric acid, which together compose more than 50% of SPE.12) The aim of this study is to investigate binding activities for pharmacologically relevant (a 1 -adrenergic, muscarinic, 1,4-DHP calcium channel antagonist) receptors of major fatty acids contained in SPE. In addition, with a newly developed method using LC/MS, the effects of SPE and its fatty acids on 5a-reductase activity in the rat liver were also examined. MATERIALS AND METHODSMaterials SPE (Serenoa repens purified extract) was kindly provided by Indena Japan (Tokyo, Japan). SPE was obtained with hypercritical CO 2 (SABAL SELECT, Indena S.p.A., Milan, Italy). The constituents contained in SPE are presented elsewhere.12) Oleic acid, lauric acid, myristic acid, palmitic acid and linoleic acid were purchased from Tokyo Chemical Industry (Tokyo, Japan), Nacalai Tesque (Kyoto, Japan), Sigma-Aldrich (St. Louis, MO, U.S.A.) and Wako Pure Chemicals (Osaka, Japan), respectively. [ Animals Male and female Sprague-Dawley rats at 8-10 weeks of age (Japan SLC Inc., Shizuoka, Japan) were housed in the laboratory with free access to a normal diet (CE-2, CREA Japan Inc., Tokyo, Japan) and water, and maintained on a 12-h light-dark cycle in a room with controlled temperature and humidity. The study was conducted in accordance with the guidelines of the Experimental Ani- to bind a a 1 -adrenergic, muscarinic and 1,4-dihydropyridine (1,4-DHP The results suggest that lauric acid and oleic acid bind noncompetitively to a a 1 -adrenergic, muscarinic and 1,4-DHP calcium channel antagonist...

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Structure-Activity Relationships of Receptor Binding of 1,4-Dihydropyridine Derivatives

Cited by 21 publications

References 20 publications

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

The effect of bromine scanning around the phenyl group of 4-phenylquinolone derivatives

Pharmacologically Relevant Receptor Binding Characteristics and 5.ALPHA.-Reductase Inhibitory Activity of Free Fatty Acids Contained in Saw Palmetto Extract

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