Review Article | Published:

Capturing adenylyl cyclases as potential drug targets

Nature Reviews Drug Discovery volume 8, pages 321335 (2009) | Download Citation

Abstract

Cyclic AMP (cAMP) is an important intracellular signalling mediator. It is generated in mammals by nine membrane-bound and one soluble adenylyl cyclases (ACs), each with distinct regulation and expression patterns. Although many drugs inhibit or stimulate AC activity through the respective upstream G-protein coupled receptors (for example, opioid or beta-adrenergic receptors), ACs themselves have not been major drug targets. Over the past decade studies on the physiological functions of the different mammalian AC isoforms as well as advances in the development of isoform-selective AC inhibitors and activators suggest that ACs could be useful drug targets. Here we discuss the therapeutic potential of isoform-selective compounds in various clinical settings, including neuropathic pain, neurodegenerative disorders, congestive heart failure, asthma and male contraception.

Key points

  • Cyclic AMP (cAMP) is generated by nine membrane-bound adenylyl cyclases (AC1–AC9) and one soluble isoform (sAC). Many drugs target cAMP signalling pathways through their respective G-protein coupled receptors. Recent studies on the physiological functions of the different AC isoforms and advances in the development of isoform-selective AC inhibitors and activators suggest that ACs are useful drug targets.

  • Genetic deletion of AC5 markedly attenuates pain-like responses in acute, inflammatory and neuropathic pain tests as well as the analgesic effects of morphine, suggesting that this isoform could be a target for the development of analgesics. Additionally, in mice, AC5 deletion increases the median lifespan, protects from reduced bone density and from aging-induced cardiomyopathy.

  • AC1 is required in learning and memory processes. Its overexpression in the forebrain increases memory for object recognition and slows rates of extinction for contextual memory, indicating that activation of AC1 enhances memory formation.

  • Cardiac-directed overexpression of AC6 improves cardiac function and has favourable effects on the failing heart. In these mice no increase in heart rate or left ventricular (LV) contractile function was observed in the basal state but a marked increase in the stimulated heart rate and the contractile function were found. In addition, a reduced mortality and improvements in measures of LV systolic and diastolic function after myocardial infarction were observed.

  • Classical anti-obstructive drugs for the treatment of asthma such as β2-adrenergic receptor agonists (fenoterol or albuterol, for example) or theophylline act through increased levels of cAMP. AC9 loss-of-function polymorphisms are involved in the decreased responsiveness to asthma therapies, suggesting that selective activation of AC9 in the lung might have bronchodilatative effects.

  • Soluble AC (sAC) is mainly expressed in the testes and pharmacological inhibition or genetic deletion of sAC markedly impairs the ability of mouse sperm to undergo capacitation. The finding that male sAC knockout mice were phenotypically normal except for their reduced fertility makes sAC an excellent target for male contraceptives.

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Acknowledgements

The work was supported by the DFG (SCHO817-1/-2, Excellence Cluster Cardio-Pulmonary System (ECCPS)) and the LOEWE Lipid Signalling Forschungszentrum Frankfurt (LiFF).

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Affiliations

  1. Pharmazentrum Frankfurt, ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

    • Sandra Pierre
    • , Gerd Geisslinger
    •  & Klaus Scholich
  2. Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

    • Thomas Eschenhagen

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Corresponding author

Correspondence to Klaus Scholich.

Glossary

Nociception

Neuronal processing of painful (noxious) stimuli.

Hyperalgesia

An increased response or sensitivity to a painful stimulus.

NSAID

(Non-steroidal anti-inflammatory drug). Drug family that is classically used for their anti-inflammatory, antihyperalgesic, and antipyretic effects.

Allodynia

Pain resulting from a stimulus that does normally not cause pain.

Dependence

A state in which the body relies on a substance for normal functioning and develops physical and/or psychological dependence.

Withdrawal

Refers to symptoms that appear when a drug that causes physical or psychological dependence is discontinued after regular and long-term use.

Hypertrophy

Increase of the size of an organ or of a selected area of tissue.

Complete Freund's Adjuvant

A suspension of desiccated Mycobacterium butyricum in a mixture of paraffin oil and an emulsifying agent, mannide mono-oleate, that is used to induce a strong and long-lasting inflammatory response in animals.

LTP

(Long-term potentiation).The prolonged strengthening of synaptic communication, induced by patterned input. It is thought to be involved in learning and memory formation.

Excitotoxicity

Process in which nerve cells are damaged and killed after overstimulation by excitatory neurotransmitters.

Desensitization

Loss of responsiveness to the continuing or increasing dose of a drug. Desensitization of G-protein coupled receptors comprise internalization and/or downregulation of the respective receptors.

Catecholamine

Natural and chemical compounds based on the amino-acid tyrosine, such as adrenaline, noradrenaline and dopamine. They activate G-protein coupled receptors and can regulate intracellular cAMP levels.

Decompensated heart failure

Failure of the heart to maintain adequate blood circulation, often a consequence of myocardial infarction, longstanding hypertension, dysfunction of heart valves, viral infection or gene mutations.

Phospholamban

An integral membrane protein that inhibits the sarcoplasmic reticulum calcium pump (SERCA) in cardiac muscle and skeletal muscle cells. Phosphorylation by protein kinase A relieves the inhibitory effect on SERCA and thereby contributes to the positive inotropic effect of catecholamines.

Inotropic

Alterations in the force of cardiac muscle contractions. Negative inotropic agents weaken, and positive inotropic agents increase, the strength of cardiac muscle contraction.

Lead compound

Compound possessing a specific pharmacological activity whose structure modifications will allow the development of further compounds with improved pharmacological properties.

Sperm capacitation

Maturation of the spermatozoid in the female tract; it involves the destabilisation of the sperm-head membrane allowing it to penetrate and fertilize the oocyte.

Prodrug

An inactive substance that is metabolised after administration to its pharmacological active form.

BODIPY

(boron-dipyrromethene). A representative of a class of fluorescent dyes that comprise dipyrromethene complexed with a di-substituted boron atom. Coupled to forskolin, the BODIPY group increases the adenylyl cyclase selectivity of forskolin.

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DOI

https://doi.org/10.1038/nrd2827

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