Advances in Pharmacology (eBook)

M. W. Anders, J. Thomas August, Joseph T. Coyle, Ferid Murad (Herausgeber)

eBook Download: PDF | EPUB

1998 | 1. Auflage
525 Seiten
Elsevier Science (Verlag)
978-0-08-058136-1 (ISBN)

Infos

Each volume of Advances in Pharmacology provides a rich collection of reviews on timely topics. Emphasis is placed on the molecular bases of drug action, both applied and experimental.

Inhalt

Front Cover 1
Advances in Pharmacology, Volume 44 4
Copyright Page 5
Contents 6
Contributors 12
Chapter 1. Drug Therapy: The Impact of Managed Care 14
I. Introduction 14
II. Current Strategies to Contain Drug Costs 16
III. New Roles for Pharmacists 26
IV. Selecting Desirable Drug-Prescribing Strategies in Managed Care 26
V. Problems Confronting Current Strategies 33
VI. Summary 38
VII. Conclusions 39
References 40
Chapter 2. The Role of Phosphodiesterase Enzymes in Allergy and Asthma 46
I. Introduction 46
II. Property and Classification of CAMP Phosphodiesterases 47
III. Role of PDEs in Regulation of Inflammatory Cell Function 55
IV. Effects of PDE Inhibitors in Animal Models of Inflammation 65
V. Role of PDE in Atopic Disease 73
VI. Conclusion 82
References 82
Chapter 3. Modulating Protein Kinase C Signal Transduction 104
I. Introduction 104
II. Signal Transduction Networks 105
III. Structural and Biochemical Studies 109
IV. Pharmacological Probes 116
V. PKC Physiology 128
VI. Anchoring Proteins 136
VII. Prospects and Wider Implications 140
References 141
Chapter 4. Preventive Role of Renal Kallikrein–Kinin System in the Early Phase of Hypertension and Development of New Antihypertensive Drugs 160
I. Renal Kallikrein–Kinin System 162
II. Role of Renal Kallikrein–Kinin System 173
III. Reduced Function of Renal Kallikrein–Kinin System in Hypertensive Patients and Hypertensive Models 189
IV. New Approaches to Drugs against Development of Hypertension 210
V. Conclusion 217
References 218
Chapter 5. The Multienzyme PDE4 Cyclic Adenosine Monophosphate–Specific Phosphodiesterase Family: lntracellular Targeting, Regulation, and Selective Inhibition by Compounds Exerting Anti-inflammatory and Antidepressant Actions 238
I. Introduction 238
II. Molecular Cloning of PDE4 Isoenzymes 245
III. Mammalian PDE4 Gene Family 247
IV. Properties of PDE4 Isoforms 275
V. Distribution of PDE4 Isoenzymes 312
VI. PDE4 Activity in Disease States 318
VII. Pharmacological Properties of Selective PDE4 Inhibitors: Potential Clinical Roles 321
VIII. Conclusions 337
References 339
Chapter 6. Clinical Pharmacology of Systemic Antifungal Agents: A Comprehensive Review of Agents in Clinical Use, Current Investigational Compounds, and Putative Targets for Antifungal Drug Development 356
I. Introduction 356
II. Antifungal Drugs in Clinical Use 360
III. Antifungal Drugs under Clinical Investigation 408
IV. Emerging Compounds and Targets 439
V. Augmentation of Host Responses 447
VI. Conclusions 451
References 451
Index 514

Textauszug

The Role of Phosphodiesterase Enzymes in Allergy and Asthma

D. Spina; L.J. Landells; C.P. Page    The Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine, Kings College School of Medicine and Dentistry, London SE5 9PJ, England

I Introduction

Cyclic 3′5′-adenosine monophosphate (cAMP) and cyclic 3′5′-guanosine monophosphate (cGMP) are second messengers that play a pivotal role in the regulation of cell function. Cyclic nucleotide phosphodiesterases (PDEs) are responsible for the degradation of these second messengers and thus are important regulators of cell function. A variety of pharmacological, biochemical, and molecular biological studies have revealed the existence of seven diverse PDE families, which are composed of at least 15 gene products that are widely distributed throughout the body. Moreover, within each family, differential splicing and posttranslational processing account for further diversity, as evidenced by the large number of splice variants of PDE (Bolger, 1994; Beavo, 1995; Conti et al., 1995; Muller et al., 1996).

Of particular interest is the role of PDE4 in regulating the function of a variety of cells thought to participate in the inflammatory process, and there is considerable interest in the development of PDE4 inhibitors for the treatment of inflammatory diseases such as asthma (Torphy and Undem, 1991; Giembycz, 1992; Hall, 1993; Nicholson and Shahid, 1994; Beavo, 1995). This review highlights the recent advances in our understanding of the role of PDE isoenzymes in health and disease and in particular focuses on the potential utility of PDE inhibitors in the treatment of allergic diseases.

II Property and Classification of cAMP Phosphodiesterases

Cyclic nucleotide PDEs (EC 3.1.4.17) hydrolyze the phosphodiester bond of purine cyclic nucleotides (cAMP, cGMP) to the inactive metabolites, 5′-AMP and 5′-GMP, respectively. These metabolites lack the ability to activate cyclic nucleotide-dependent kinases. In general, the sequence homology between families of PDEs is between 20 and 25%, most of which reside in the catalytic domain located near the carboxy terminus. Outside the catalytic domain reside two ill-defined domains whose sequences are less conserved. It is also clear that the N-terminal domain of PDE may be regulatory sites. Thus, for PDE1 and PDE2, Ca2+/calmodulin and cGMP may alter enzyme activity as a consequence of binding to their respective regulatory sites (Beavo and Reifsnyder, 1990; Conti et al., 1991, 1995; Bolger, 1994; Beavo, 1995; Muller et al., 1996). There are seven families of genes that encode for the different PDE enzymes, whose properties, affinity for cyclic nucleotides, and selective inhibitors are summarized in Table I. Theophylline is the archetypal PDE inhibitor whose structure is shown together with other methylxanthines and enprophylline (Fig. 1).

Table I

Characteristics of Phosphodiesterase Isoenzymes

1

Ca2+/calmodulin-stimulated

1–30

3

Vinpocetine, KS-505a

2

cGMP-stimulated

50

50

EHNA

3

cGMP-inhibited

0.2

0.3

Siguazodan (SKF 94120) Milrinone Cilostamide (SKF 95654)

4

cAMP-specific

4

>100

Rolipram, RP 73401, denbufylline, CDP 840, Ro 201724, CP 80633

5

cGMP-specific

150

1

Zaprinast

6

Photoreceptor

60

>100

Zaprinast

7

High-affinity cAMP-specific

0.2

>100

None identified

Figure 1 Chemical structures of some alkylxanthine PDE inhibitors. Note that enprophyl-line lacks a methyl group on N-1 and therefore is not classified as a methylxanthine.

It is very clear that most PDE families contain several subfamilies whose members are encoded by similar homologous genes (70–90%), and within each subfamily there exists a number of PDEs that are formed from alternative mRNA splicing and posttranslational processing (Beavo and Reifsnyder, 1990; Bolger, 1994; Beavo, 1995; Conti et al., 1995; Muller et al., 1996). A brief description of the different PDE families will be given, although greater detail can be obtained from the preceding reviews.

A PDE1

Three PDE1 genes (PDE1A, PDE1B, and PDE1C) have thus far been identified. The N-terminal region of the enzyme contains the Ca2+/calmodulin binding domain, and the PDE catalytic domain is located near the carboxy terminus. The activity of the enzyme is increased subsequent to Ca2+/calmodulin binding to the regulatory site (Sharma and Wang, 1986). Expression of PDE1A and PDE1C mRNA is most abundant in human brain, heart, and kidney, while PDE1B mRNA is expressed in human brain (Loughney et al., 1996). A number of PDE1 isoforms have been isolated from bovine brain and heart and are characterized by different molecular weights and kinetic properties. Two isoforms were isolated from bovine brain (60 and 63 kDa), while the 60-kDa isoform was found in bovine heart and lung (Sharma et al., 1984; Sharma and Wang, 1986; Sharma, 1991). Kinetic data show that the isoenzymes isolated from bovine brain, heart, and lung have a higher affinity for cGMP (Km ~ 3 μM) than for cAMP (Km ~ 40 μM), although the bovine brain 63-kDA PDE has a two- to threefold higher affinity for both substrates (Sharma and Kalra, 1994).

A further isoenzyme with a higher molecular weight (150 kDa) specific for cGMP has been purified from bovine brain (Shenolikar et al., 1985). A similar enzyme isolated from rat testis (Rossi et al., 1988) and canine trachea (Torphy and Cieslinski, 1990) exhibits similar affinities for both substrates (Km ~ 1–3 μM).

B PDE2

The cGMP-stimulated PDE hydrolyzes both cAMP and cGMP. The enzyme contains a cGMP binding domain near the N-terminal region and a catalytic region near the carboxy-terminal region (Charbonneau et al., 1990). Only one gene encoding PDE2 has been identified. A bovine cDNA encoding this enzyme (103 kDa) has been isolated and shown to be expressed in heart, hippocampus, and kidney (Sonnenburg et al., 1991).

PDE2 is stimulated by cGMP, which displays a low affinity for both cAMP (30–50 μM) and cGMP (10–30 μM). Low concentrations of cGMP (0.1–5 μM) stimulate cAMP hydrolysis (Martins et al., 1982).

C PDE3

The activity of this enzyme is characterized by high affinity for both cyclic nucleotides (0.1–0.5 μM), and cGMP acts as a competitive inhibitor of cAMP hydrolysis. While the affinities of the enzyme for cAMP and cGMP are similar, it is clear that the maximum velocity (Vmax) for cAMP is four- to 10-fold higher (Torphy and Undem, 1991; Nicholson and Shahid, 1994). Two cDNAs encoding PDE3A (Meacci et al., 1992) and PDE3B (Manganiello et al., 1995) that encode a 125-kDa and 123-kDa protein, respectively, have been isolated from human tissue. PDE3A is predominantly found in smooth muscle, while PDE3B is located in adipose tissue (Reinhardt et al., 1995).

D PDE4

This family of PDE is characterized by a high affinity for cAMP hydrolysis (Km 0.5–2.0 μM) but relatively low affinity for cGMP (Km > 50 μM), with the latter having no effect on cAMP hydrolysis. The PDE4 family is composed of four different genes—PDE4A, PDE4B, PDE4C, and PDE4D— which yield mRNA transcripts of different sizes and cellular distribution (Bolger, 1994; Engels et al., 1994; Muller et al., 1996). This enzyme is inhibited by a number of structurally distinct chemicals (Fig. 2). It is now evident that these inhibitors also display some selectivity toward the PDE4 subtypes, and it is envisaged that more subtype-selective inhibitors will be discovered.

Figure 2 Chemical structures of some PDE4 inhibitors: a xanthine derivative, denbufylline; a pyrrolidinone, rolipram, and an analogue RP 73401; a tri-aryl ethane, CDP 840; and a pyrimidone, CP 80633.

1 Rolipram Binding Site

An interesting feature of PDE4 is that rolipram binds with high affinity to rat brain membranes, characterized by saturable binding to a homogeneous class of sites (Schneider et al., 1986), and the affinity of rolipram for this binding site is at least two orders of magnitude greater than its affinity for the catalytic site (Torphy et al., 1992a). These sites reside on the same gene product (Torphy et al., 1992a), and a number of studies have addressed...

Produkt-Details

• Erscheint lt. Verlag: 8.4.1998
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber ► Natur / Technik ► Natur / Ökologie
• Themenwelt: Medizin / Pharmazie ► Gesundheitsfachberufe
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Studium ► Querschnittsbereiche ► Infektiologie / Immunologie
• Themenwelt: Naturwissenschaften ► Biologie ► Biochemie
• Themenwelt: Naturwissenschaften ► Biologie ► Humanbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• Themenwelt: Naturwissenschaften ► Physik / Astronomie ► Angewandte Physik
• Themenwelt: Technik
• ISBN-10: 0-08-058136-6 / 0080581366
• ISBN-13: 978-0-08-058136-1 / 9780080581361