Structural Analysis of Drug Molecules in Biological Membranes

Herbette, Leo G.; Chester, David W.; Rhodes, David G.

doi:10.1016/s0006-3495(86)83605-0

Cited by 112 publications

(74 citation statements)

References 4 publications

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“…Dihydropyridinetype calcium channel blockers are lipophilic in general, 49,50) and are believed to exert their effects by a two-stage binding mechanism that involves partitioning of the drugs into the lipid bilayer of cell membrane, with subsequent lateral diffusion to the receptor binding site. [51][52][53] Herbette and Katz cal- culated that even at an nM aqueous concentration of nimodipine, which is less lipophilic than benidipine 54) or amlodipine, 55) the "membrane" concentration is 10 4 -fold higher than in the aqueous medium. 50) Therefore, in the longer period of incubation, the three drugs we used probably accumulated in plasma membranes, resulting in their higher concentrations in the vicinity of calcium channels.…”

Section: Discussionmentioning

confidence: 99%

Effects of Various Antihypertensive Drugs on the Function of Osteoblast.

Nishiya

Sugimoto

2001

Biological & Pharmaceutical Bulletin

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Several studies have suggested that high blood pressure is associated with abnormalities in calcium metabolism, leading to increased calcium loss, secondary activation of the parathyroid gland, and increased removal of calcium from bone. [1][2][3][4][5][6][7] Consistently, studies in hypertensive rats have shown that hypercalciuria and ensuing hyperparathyroidism lead to reduced growth and detectable decrease in total bonemineral content later in life. 8,9) Recently, it was also shown that higher blood pressure in elderly white women is statistically associated with increased bone loss at the femoral neck, which may contribute to bone fracture. 10) Drugs used as primary choice for the treatment of hypertension include calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor type1 (AT1) antagonists, diuretics, b-blockers, and a-blockers. 11) The first three drugs are especially widely used in Japan. The mechanism by which each drug lowers blood pressure differs. Calcium channel blockers primarily inhibit calcium influx through the L-type voltage-dependent calcium channel at the level of vascular smooth muscle, thereby disrupting the excitation contraction process. 12,13) Both ACE inhibitors and AT1 antagonists interfere with the renin-angiotensin system (RAS). The former inactivates the conversion of angiotensin I into angiotensin II (Ang II), which is a vasoconstrictive peptide, while the latter blocks the binding of Ang II to its receptor. 14,15) Osteoblasts are derived from mesenchymal stem cells and play a pivotal role in bone formation. During differentiation, they first express type I collagen, then alkaline phosphatase (ALP), and other bone matrix proteins and finally form mineralized bone. Osteoblasts express voltage-dependent calcium channels. 16) Various bone regulatory factors such as vitamin D 3 , [17][18][19] parathyroid hormone, 17,20,21) and prostaglandin E 2 17,22) cause a rise in intracellular calcium concentration ([Ca 2ϩ ] i ), at least part of which is decreased by dihydropyridine-type calcium channel blockers. These factors also promote or inhibit osteoblast differentiation. [23][24][25][26] Thus, it is suggested that signaling through the L-type calcium channel may be important for osteoblast functions. However, the fact that these factors give rise to multiple signals independent of calcium influx (i.e., transcription of specific genes, 27) cAMP production, 20,28) release of calcium ion from intracellular store 17) ) obscures the role of L-type calcium channel. Recently, Kosaka and Uchii found that a calcium channel blocker benidipine, but not amlodipine or nifedipine, increased ALP activity of osteoblastic cells isolated from neonatal mouse calvaria. 29) We further investigated the effects of benidipine on osteoblastic functions using osteoblastic cell line MC3T3-E1, 30) which is widely used in studies on various aspects of osteoblast differentiation since it expresses osteoblast markers and forms a mineralized extracellular matrix. 31,32) There we ...

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Section: Discussionmentioning

confidence: 99%

Effects of Various Antihypertensive Drugs on the Function of Osteoblast.

Nishiya

Sugimoto

2001

Biological & Pharmaceutical Bulletin

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“…Our hypothesis is strengthened further by recent data suggesting a similar covalent interaction between the cysteine 47 and an anandamide derivative carrying an isothiocyanate group at its terminal C-20 carbon. 3 …”

Section: How Anandamide Reaches Its Active Site At the Cb1 Receptormentioning

confidence: 99%

“…Accumulated evidence indicates that many fatty acid-derived lipophilic neurotransmitters are synthesized, stored, and degraded and also exert their functions within the lipid membrane (1,2). Therefore, it has been suggested that the conformation, location, and orientation of the ligand in the membrane are critical in determining its ability to reach and interact productively with its site of action (3)(4)(5). Exploring the conformational and dynamic properties of these ligands in the membrane can lead to a better understanding of the molecular features involved in their interactions with the target proteins (6).…”

mentioning

confidence: 99%

The Conformation, Location, and Dynamic Properties of the Endocannabinoid Ligand Anandamide in a Membrane Bilayer

Tian

Guo

Yao

et al. 2005

Journal of Biological Chemistry

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The endogenous cannabinoid ligand anandamide is biosynthesized from membrane phospholipid precursors and is believed to reach its sites of action on the CB1 and CB2 receptors through fast lateral diffusion within the cell membrane. To gain a better insight on the stereochemical features of its association with the cell membrane and its interaction with the cannabinoid receptors, we have studied its conformation, location, and dynamic properties in a dipalmitoylphosphatidylcholine multilamellar model membrane bilayer system. By exploiting the bilayer lattice as an internal threedimensional reference grid, the conformation and location of anandamide were determined by measuring selected inter-and intramolecular distances between strategically introduced isotopic labels using the rotational echo double resonance (REDOR) NMR method. A molecular model was proposed to represent the structural features of our anandamide/lipid system and was subsequently used in calculating the multispin dephasing curves. Our results demonstrate that anandamide adopts an extended conformation within the membrane with its headgroup at the level of the phospholipid polar group and its terminal methyl group near the bilayer center. Parallel static 2 H NMR experiments further confirmed these findings and provided evidence that anandamide experiences dynamic properties similar to those of the membrane phospholipids and produces no perturbation to the bilayer. Our results are congruent with a hypothesis that anandamide approaches its binding site by laterally diffusing within one membrane leaflet in an extended conformation and interacts with a hydrophobic groove formed by helices 3 and 6 of CB1, where its terminal carbon is positioned close to a key cysteine residue in helix 6 leading to receptor activation.The membrane lipid bilayer is a ubiquitous molecular assembly into which are embedded a variety of proteins, natural hormones, and neurotransmitters. Accumulated evidence indicates that many fatty acid-derived lipophilic neurotransmitters are synthesized, stored, and degraded and also exert their functions within the lipid membrane (1, 2). Therefore, it has been suggested that the conformation, location, and orientation of the ligand in the membrane are critical in determining its ability to reach and interact productively with its site of action (3-5). Exploring the conformational and dynamic properties of these ligands in the membrane can lead to a better understanding of the molecular features involved in their interactions with the target proteins (6).N-Arachidonoylethanolamine (anandamide), initially isolated from mammalian brain, has been identified as an endogenous ligand for the two known G protein-coupled cannabinoid receptors (CB1 and CB2) (7). This endocannabinoid exerts its activity by modulating several physiological functions such as pain, cognition, and memory. Site-directed mutagenesis evidence has shown that the anandamide binding sites are embedded in the trans-membrane helices of the receptor (8, 9). This correlates wel...

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“…As argued below, it is the physicochemical nature of the interactions of formoterol or salmeterol with the membrane lipid bilayer that may determine the duration of action and other behaviours of these molecules in vitro and in vivo. It should be stressed at this point that lipophilicity (octanol:water partition) and membrane lipid bilayer affinity (Kp (mem) ) are by no means identical, and the octanol:water partition coefficient is only a crude predictor of the true extent of drug interactions with biological membranes [18][19][20].…”

Section: Pharmacological and Physicochemical Properties Of Formoterolmentioning

confidence: 99%

Why are long-acting beta-adrenoceptor agonists long-acting?

Anderson¹,

Lindén²,

Rabe³

1994

Eur Respir J

221

159

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The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.

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Structural Analysis of Drug Molecules in Biological Membranes

Cited by 112 publications

References 4 publications

Effects of Various Antihypertensive Drugs on the Function of Osteoblast.

Effects of Various Antihypertensive Drugs on the Function of Osteoblast.

The Conformation, Location, and Dynamic Properties of the Endocannabinoid Ligand Anandamide in a Membrane Bilayer

Why are long-acting beta-adrenoceptor agonists long-acting?

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