PHARMACOLOGYProceedings of the Xth International Congress ofPharmacology (IUPHAR), Sydney, 23-28 August 1987

Editors:

M.J. RandDepartment of Pharmacology,University of Melbourne,Parkville, Victoria, Australia

C. RaperSchool of Pharmacology,Victorian College of Pharmacy,Parkville, Victoria, Australia

E4M 1987

EXCERPTA MEDICA, Amsterdam - New York - Oxford

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Contents

Noradrenergic function

Presynaptic a2-autoinhibition in vascular neuroeffector junctions in whichnoradrenaline and ATP are co-transmitters

K. Starke, I. Von Kugelgen, J. T. Regenold and P. Illes 3Disposition of noradrenaline at the sympathetic neuro-effector junction

W. Osswald 7Molecular mechanisms and regulation of alphai-adrenergic receptors

P.A. Insel, B.I. Terman, S.R. Slivka, R.J. Hughes, J.J. Waite,K.E. Meier and M.J. Howard 13

Molecular mechanisms of /3-adrenergic receptor regulationJ.M. Stadel, M.T. Nakada and S.T. Crooke 17

Endocrine disorders and cardiac adrenoceptor functionJ.H. McNeil! 21

Adrenoceptors, vascular reactivity and hypertensionJ.L. Reid 27

Possible sites and mechanisms whereby urapidil and its analogue B695-40exert CNS mediated hypotensivev effects

R.A. Gillis, K. Hill, J.S. Kirby, A. Martino-Barrows, P.J. Gatti,J.A. Quest, W.P. Norman and K.J. Kellar 31

Effects of alpha-adrenoceptor antagonists on central sympathetic outflowA.G. Ramage 37

Clonidine acts on imidazole receptors in brain which bind an endogenousclonidine-displacing substance

D.J. Reis, P. Ernsberger and M.P. Meeley 41Demonstration of the central hypotensive activity of a i -adrenoceptorantagonists. Focus on urapidil \

P.A. Van Zwieten, M.J. Mathy and H.N. Doods 47

Cholinergic function

Biochemical evidence for muscarinic receptor subtypesJ. Heller Brown, D. Goldstein and S. Brown Masters 55

Selective muscarinic antagonist for peripheral muscarinic receptor subtypesH.N. Doods 59

Structure-activity relationships of drugs acting selectively at differentmuscarinic receptors

E. Mutschler, G. Gmelin, U. Moser, J. Wess and G. Lambrecht 67Modulation of muscarinic receptors by interactions with G-protein(s) andNa+-channels

M. Sokolovsky, E. Moscona-Amir, M. Cohen-Armon, H. Garty andY.I. Henis 77

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Nicotinic and muscarinic M2 receptor alterations in the cerebral cortex ofpatients with senile dementia of the Alzheimer's type (SDAT)

J.X. Wang, W.R. Roeske, L. Mei, E. Malatynska, W. Wang,E.K. Perry, R.H. Perry and H.I. Yamamura 83

Block of open ion channels as a mechanism of postsynaptic antagonismD.G. Ogden 87

Prejunctional nicotinic cholinoceptors at the neuromuscular junction inskeletal muscle.

W.C. Bowman, A.J. Gibb, A.J. Harborne and I.G. Marshall 91Antimuscarinic activity of neuromuscular blocking agents

D.A. Kharkevich and V.A. Shorr 95A clinician looks at the pharmacokinetics and pharmacodynamics ofneuromuscular blocking drugs

T.A. Torda, G.G. Graham and B.L. Love 99

Amino acid transmitters

Excitatory amino acids as vertebrate excitatory transmittersH. McLennan 105

Sigma opiates as excitatory amino acid antagonistsD. Lodge 109

Molecular pharmacology of excitatory amino acid receptors:Conformational and stereochemical requirements

P. Krogsgaard-Larsen, U. Madsen, B. Nielsen, J.J. Hansen,E.0. Nielsen, L. Brehm and D.R. Curtis 113

Pharmacology and neuroprotective effects of the NMDA antagonistMK-801

L.L. Iversen, G.N. Woodruff, J.A. Kemp, A. Foster, R. Gill andE. Wong 117

Stress, steroids and GABA receptorsG.A.R. Johnston, D.I.B. Kerr and J. Ong 121

Modulation of GABA receptor interaction with GABA uptake inhibitorsC. Braestrup, E.B. Nielsen, K.H. Wolffbrandt, K.E. Andersen,L.J.S. Knutsen and U. Sonnewald 125

Allosteric modulation at the GABAA (GABA/benzodiazepine) receptor:Role of endogenous ligands of benzodiazepine recognition sites

A. Guidotti 129Biochemical properties of the GABA receptor-chloride channel complex

R.W. Olsen, G.B. Stauber, R.W. Ransom, A.I. Dilber, L. Deng,M. Bureau, G. Smith, M. Khrestchatisky and A.J. Tobin 133

Development of GABA/benzodiazepine receptor complex in cerebralcortical neurons in primary culture

K. Kuriyama, S. Ohkuma and M. Kishi 137

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New aspects of neurotransmission

Antidepressant drugs and monoamine transport systems: Relevance to theirmechanism of action

S.Z. Longer, E. Habert and D. Graham 143Searching for the non-adrenergic non-cholinergic autonomic transmitter

J.S. Gillespie 161

Peptide neurohormones and peptide autacoids

Neuropeptide generation, CNS effects and mode of actionD. De Wied 173

Interfacing molecular biology and cardiovascular control: Angiotensin andother neuropeptides

D. Ganten, K. Lindpaintner, R.E. Lang and T. Unger 185Atriopeptin metabolism

M.L. Michener, A.G. Wilson and P. Needleman 195Renal actions of atrial natriuretic peptide

T.O. Morgan, P.J. Harris, J. Zhuo and D. Thomas 201Localization and action of atrial natriuretic polypeptide in the brain

H. Imura, K. Nakao, H. Itoh, T. Yamada, N. Morii, S. Shiono,A. Sugawara, Y. Saito, M. Mukoyama, H. Arai, M. Sakamoto and

K. Hosoda 207The roles of neuropeptides in spinal nociceptive mechanisms: Newapproaches using isolated CNS preparation

M. Otsuka and M. Yanagisawa 211The design of peptide analogs for pharmacology

D.F. Veber and R.M. Freidinger 215Endocrine regulations mediated by capsaicin-sensitive afferent neurons

F. Lembeck, R. Amann and J. Donnerer 219

Opiates and opioid peptides

Mechanism of morphine analgesia and hybridization approaches to studythe role of opioid peptides in acupuncture

K. Tsou 225Molecular basis of acute and chronic effects of opioids

H.H. Loh 235Mechanisms of opioid tolerance and dependence

R. Schulz 239

Purines

Dual control of blood pressure by purinesG. Burnstock 245

Agonists and antagonists for adenosine receptorsU. Schwabe 255

Quantal release of transmitter from sympathetic nerve terminalsT. Cunnane 259

Evidence for the role of ATP as a cotransmitterD.P. Westfall 263

Presynaptic inhibitory actions of adenosine on peripheral adrenergic andcholinergic neurotransmission

D.M. Paton 267Mechanisms of interaction between adenosine and other compounds

B.B. Fredholm, C. Nordstedt, I. Van der Ploeg, T. Dunwiddie, J. Wang,M. Duner-Engstrom, E. Lindgren and J. Fast bom 271

Serotonin

Classification of functional 5-hydroxytryptamine receptorsP.P.A. Humphrey and W. Feniuk 277

Second messenger systems linked to different serotonin (5-HT) receptorsM. Hamon 281

Excitatory actions of 5-HT on peripheral and central neuronesJ.R. Fozard 285

Inhibitory actions of serotonin (5-HT) on peripheral and central neuronesM. Gothert 289

Receptors mediating cardiac and vascular effects of serotoninM.L. Cohen 295

Behavioural actions of 5-HTM.D. Tricklebank 299

Non-classical autacoid mediators

Evidence for PAF as a mediator of asthmaC.P. Page and D.N. Robertson 305

PAF-acether in inflammation and experimental asthmaM. Bachelet, M. Bureau, M. Chignard, E. Coeffier, R.B. Cordeiro,S. Desquand, C. Dumarey, F. Fouque, D. Joseph, V. Lagente,A. Lellouch-Tubiana, J. Lefort, E. Malanchere, M.A. Martins,M. Pretolani, J. Randon, M. Schattner, P.M.R. Silva, L. Touqui,E. Vannier and B.B. Vargaftig 311

Involvement of platelet-activating factor (PAF) in cerebral post ischemicphase in the Mongolian gerbil

B. Spinnewyn, N. Blavet, F. Clostre and P. Braquet 317Leukotriene receptors and receptor antagonists

A. W. Ford-Hutchinson 321

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Arachidonate 5-lipoxygenase and its selective inhibitorsS. Yamamoto, N. Veda, S. Kaneko, C. Yokoyama, T. Tonai,T. Yoshimoto, M. Ban, K. Matsumoto and T. Horie 325

Leukotrienes and the cardiovascular systemP.J. Piper, J. W. Antoniw, H. Bin Yaacob and A. W.B. Stanton 329

The pharmacological properties of a novel series of selective inhibitors ofarachidonate 5-lipoxygenase

P. Bhattacherjee, R.L. Follenfant, L.G. Garland, C.A. Higgs, P.R. Islip,W.P. Jackson, S. Moncada, A.N. Payne, R. W. Randall, C.H. Reynolds,J.A. Salmon, J.E. Tateson and B.J.R. Whittle 333

The actions of leukotriene agonists, antagonists and synthesis inhibitors inman

N. Barnes, J. Evans, J. Zakrzewski, P. Piper and J. Costello 337Additional evidence that endothelium-derived relaxing factor is nitric oxide

M. T. Khan and R.F. Furchgott 341Properties of endothelium-derived relaxing factor (EDRF) released fromcultured endothelial cells

T.M. Cocks, J.A. Angus and B. Grego 345Chemical reactivity of endothelium-derived relaxing factor

G.M. Rubanyi 351The mechanism of relaxation of EDRF: Similarities of the effects of EDRFand nitrovasodilators on cyclic GMP formation and vascular relaxation

F. Murad 355Mechanisms of production and action of endothelium-derived relaxingfactor

U. Forstermann 359Evidence that the inactive form of inhibitory factor is nitrite and theacid-activated form is nitric oxide

W. Martin, J.A. Smith, M.J. Lewis and A.H. Henderson 363

Receptors and receptor activation-response coupling

The brain slice comes of age: The action of drugs on single neurones reveala multitude of currents underlying neuronal excitability

J.S. Kelly 369The intronless gene for the /32-adrenergic receptor: A comparison withgenes for other G protein coupled receptors

B.K. Kobilka, T. Frielle, J. W. Regan, T.S. Kobilka, M.B. Caron andJ.F. Lefkowitz 111

Functional analysis of cloned human mineralocorticoid receptorJ.L. Arriza and R.M. Evans 381

Steroid receptors and their homologies to oncogenesZ. Krozowski 385

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Molecular biology and evolution of adrenergic and muscarinic cholinergicreceptors

J.C. Venter, CM. Eraser, F.Z. Chung, J.D. Gocayne, M.G. Fitzgerald,K.U. Lentes, A.R. Kerlavage, D.A. Robinson, J. Lai and P.C. Potter 389

Myosin phosphorylation inhibitors and vascular contractionH. Hidaka and T. Tanaka 393

Catecholamine-induced desinsitization and down-regulation of B-adrenergicreceptor function

J.P. Perkins and C. Hertel 401Inositol polyphosphates and receptor activation in brain

S.R. Nahorski, I.H. Batty, T.A. Rooney and J. Baird 407G-protein-regulated phospholipase C: The turkey erythrocyte membrane asa model system

T.K. Harden, C.P. Berrie, J.L. Boyer, P.T. Hawkins, J.R. Hepler,M. W. Martin, J.M. May, A.J. Morris, L. Stephens, G.L. Waldo andC.P. Downes 411

Second messenger modulation of neuronal calcium currentS.G. Rane 415

Mapping second messenger systems in the brainJ.M. Baraban, P.F. Worley, S. Supattapone, K.R. Stratton andS.H. Snyder 419

Respiratory tract pharmacology

Modulation of neuropeptide actions by enkephalinaseJ.A. Nadel and D.B. Borson 425

Pharmacokinetic and metabolic properties of the pulmonary circulationY.S. Bakhle 441

Airway actions of 'bronchodilators'C.G.A. Persson . 451

Receptors in airway smooth muscleP.J. Barnes 455

Mechanisms contributing to bacterial endotoxin-induced bronchialhyperreactivity in the guinea pig

F.P. Nijkamp, P.A.J. Henricks, F. Engels, A.J.M. Van Oosterhout andG. Folkerts . 461

The status of beta-adrenoceptor function in asthmaR.G. Goldie, D. Spina, K.M. Lulich and J.W. Paterson 465

Molecular mechanism of modulation of 0-adrenergic function in the airwayby glucocorticoids

F.F. Hirata 469

Cardiovascular pharmacology

Inotropic agents: New positive inotropic agents and their mechanism of actionN. Taira All

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Alpha-adrenoceptor stimulation and positive inotropyH. Scholz, M. Nose, W. Schmitz, J. Scholz, M. Steinfath, V. Steinkrausand K. Thormdhlen 481

New water soluble forskolin derivatives: Cardiovascular activityA.N. Dohadwalla 485

Inotropic and vasodilator drugs for heart failure in manG. Jennings, I. Meredith, G. Hasking and Y. Lim 489

Recent developments in Class I antiarrhythmic drug: Clinical relevance ofdifferences in kinetics of interaction with sodium channels

T.J. Campbell 493Correlation between the antiarrhythmic effects of drugs on experimentalventricular arrhythmias and their cellular electrophysiological effects

K. Hashimoto 497Eicosanoids and cardiac arrhythmias

J.R. Parratt, C.L. Wainwright and S.J. Coker 501Calcium channels: Properties, modulation and functional significance

H. Reuter 507L-type calcium channels: Molecular aspects

H. Glossmann, J. Striessnig, H.-G. Knaus, M. Grabner, M. Schirmer,E. Meusburger, L. Hymel and H.-G. Schindler 509

New approaches to tissue specificity of calcium channel blockersT. Godfraind, N. Morel and M. Wibo 513

Antihypertensive and tissue protective effects of nitrendipineA. Knorr, C. Hirth, J.-P. Stasch, S. Kazda and G. Luckhaus 517

Effects of calcium antagonists on venous complianceW.H. Aellig 523

Interactions between calcium entry blockers and vascular a-adrenoceptorsP.A. Van Zwieten and P.B.M. W.M. Timmermans 527

Mode of action of ACE inhibitors: Plasma and tissue inhibitionC.I. Johnston, R. Cubela, K. Sakaguchi, P. Phillips, S.Y. Chai,F.A. Mendelsohn and B. Jackson 537

Metabolism and pharmacodynamics of angiotensin converting enzymeinhibitors with special reference to perindopril

O.H. Drummer, K. Rowley, H. Johnson, P. Worland, B. Workman,Q.L.G. Harris, E.L. Conway and W.J. Louis 545

Mineralocorticoid and glucocorticoid antagonists in experimental andclinical hypertension

M. Worcel and A.-M. Moura 551Physiological mechanisms involved in steroid induced hypertension

B.A. Scoggins, J.P. Coghlan, D.A. Denton, A.F. Reid, CD. Spence andJ.A. Whitworth 557

Steroid receptors and blood pressure regulationJ. W. Funder 561

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Molecular biology, biotechnology and drug development

Location of gene expression in mammalian cells: Impact for pharmacologyJ.P. Coghlan, J.D. Penschow, B. Oldfield, P. Roche, R. Richards,B. Evans, L. Nicholson, C. Spence, J. Haralambidis and G. W. Tregear 567

Therapeutic potential of interleukin 2 and cultured T cellsM.A. Cheever, J.P. Klarnet and P.D. Greenberg 577

Macrophage modulation and functions in cancer therapeutics:Muramyldipeptides (MDPs) and their derivatives

H. Frost and G. Schumann 581Clinical potential of haemopoietic growth factors (colony stimulatingfactors)

G. Morstyn, L. Campbell, J. Cebon, A.W. Burgess and R. Fox 585Recombinant proteins open new dimensions in pharmaceutical research:The interleukin-2 pathway

L.P. Gage 589Regulatory perspectives on biotechnology derived products

E. Esber, B. Burlington and J. Weissinger 595Successful applications of QSAR in drug design practice

T. Fujita 603Receptor-based drug design

P. Goodford 607Comparative molecular modelling of adrenergic vs dopaminergic receptors

Y.C. Martin, E.B. Danaher, L. Kauslauskas and K.H. Kim 611The use of isolated epithelial and cultured endothelial cells to elucidatedrug transport mechanisms

K.L. Audus and R.T. Borchardt 615Physiological aspects of small particle delivery systems

L. Ilium and S.S. Davis 619The use of cytotoxic-drug antibody immunoconjugates for the treatment ofcancer

I.F.C. McKenzie, M.J. Smyth, Z. Cunningham and G.A. Pietersz 625

Chemotherapy

Strategies in the development of antiviral agentsE. De Clercq 631

A new class of chemotherapeutic agents: Inhibitors of polyaminebiosynthesis

A. Sjoerdsma 643Eicosanoid inhibition as a novel approach towards chemoprophylaxis inschistosomiasis

B. Salafsky and A. Fusco 653Pharmacological studies on artemisinin and its derivatives as antimalarials

H.M. Gu 657

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Discovery and development of a new antimalarial hydroxynaphthoquinoneV.S. Latter 661

Recent approaches to the chemotherapy of leishmaniasisS.L. Croft 665

Ivermectin: A review of its use in onchocerciasisM.A. Aziz, E. Rupp, D. Neu and A. Ko 669

Pharmacological aspects of anti-herpes agentsW.H. Prusoff and T.S. Lin 673

Varied biological properties of influenza viruses with amino acid sequencechanges in the receptor binding areas of the HA

J.S. Oxford 677New interferons and prospects for use

B. Cheetham, M. Beilharz, P. Chambers, P. Hertzog, B. Mclnnes,G. McMullen, S. Marzuki, M. Tymms, CJ. Burrell, Ar Jilbert andA. W. Linnane 683

Structure-activity relationship of peptides inhibiting the ribonucleotidereductase of herpes simplex

P. Gaudreau, J. Michaud, Y. Langelier and P. Brazeau 687

Retinoids

Molecular mechanism of retinoid actionF. Chytil 693

Effects of retinoids on the epidermisP.M. Elias 697

Antiinflammatory activity of retinoids in animal modelsJ.W. Coffey, C Fiedler-Nagy, S.M. Weisman, W.C. Hope andA.F. Welton 705

Fertility control

Long acting progestogensI.S. Eraser 711

Highlights of contraceptive research in ChinaXiao Bilian and Lei Haipeng 715

Vaccine contraceptivesW.R. Jones 721

Drugs to reduce alcohol consumption

Basic neurochemical mechanisms of modulation of alcohol consumption inthe P and NP rats

L. Lumeng, J.M. Murphy, W.J. McBride and T.K. Li 727

XVI

Selectivity of serotoninergic drugs to reduce alcohol consumption. Bench tobedside: Strategies and pitfalls

R.A. Deitrich 731Clinical trials for testing new drugs to decrease alcohol consumption

C.A. Naranjo and E.M. Sellers 111Studies on different types of 5-HT uptake blockers to identify themechanisms involved in ethanol intake in the rat

S.O. Ogren and Z. Amit 741Catecholamine-ethanol interactions in humans and animals

D. Nutt, I. Mefford, P. Glue, R. Lister and M. Linnoila 745

Drug metabolism and drug development

Developmental pharmacologyW. Klinger, D. Miiller, U. Kleeberg, F. Jahn and R. Glockner 753

Commonality of cytochromes P-450: Structural and functional similaritiesbetween hydroxylases metabolizing xenobiotic and endogenous substrates

M.R. Waterman 765Molecular evolution of cytochrome P-450 super-family: Comparison of theprimary structures

Y. Fujii-Kuriyama, K. Sogawa and O. Gotoh 111Extra-hepatic cytochrome P-450 isozymes

R. Gasser and R.M. Philpot 775Human liver cytochrome P-450 enzymes involved in the oxidation ofxenobiotic compounds

F.P. Guengerich, C Ged, T. Muto, D.R. Umbenhauer, R. W. Bork,M.V. Martin, G.A. Dannan, W.R. Brian andR.S. Lloyd 779

Isozymes of UDP-glucuronyl transferase in rats and man and theirinduction by xenobiotics

K. W. Bock and G. Schirmer 783Enantioselectivity: Its biological basis and pharmacological consequences

R.R. Ruffolo Jr 787Mechanisms of enantioselective drug metabolism

B. Testa 791Inversion of enantiomers: 2-arylpropionic acid anti-inflammatory drugs

K. Williams 795Pharmacokinetic consequences of enantioselective drug disposition

M. Eichelbaum 799Pharmacodynamic consequences of enantioselective drug disposition

T.F. Blaschke and K.M. Giacomini 803Explicit notation system for stereoisomeric drugs

M. Simonyi 807Effect of zinc- and tin-protoporphyrin on gluthathione metabolism in ratorgans

M.D. Maines 809

XV11

Alteration of drug metabolism by vanadiumG.F. Fuhrmann, M. Bruech and K.J. Netter 813

Acute depletion of pulmonary lavage cells and enhanced lipid peroxidationin alveolar macrophages following parenteral administration of nickelchloride to rats

F. W. Sunderman Jr, L.L. An, O. Zaharia, S.H. Y. Wong andS.M. Hopfer 817

Toxicology and toxinology

Neurobehavioral toxicologyG. Zbinden 823

Patterns of structural change in DNA in vivo and tumorigenicity asindicators of genotoxicity

B. W. Stewart and M. Haber 833The place of whole-animal tests in genotoxicity test batteries

J. Bootman 837Quantitative evaluation of genotoxic potency of chemicals in a batterysystem combining with in vitro and in vivo tests

M. Ishidata Jr, T. Sofuni and M. Hayashi 841Laboratory and epidemiological studies of human carcinogenesis

C.C Harris and B.F. Trump 845Role and dietary regulation of peroxisomal and mitochondrial fatty acidoxidation

G.P. Mannaerts and P.P. Van Veldhoven 853Localization and modulation of dolichol synthesis in liver peroxisomes

E.-L. Appelkvist and G. Dallner 857Voltage-activated ion channels as a target of natural toxins

T. Narahashi 863Pharmacology of Australian spider venoms

E.J. Mylecharane \ 867Cobrotoxin structure and function

C.C. Yang 871Mechanistic studies on the MPTP inactivation of MAO B

N. Castagnoli Jr, A. Sparatore, S. Ottoboni, L. Leng and A. Trevor 875Assessing brain catecholamine metabolism: Alterations in MPTP-inducedParkinsonism

I.J. Kopin, K. Bankiewicz and J. Harvey-White 879MAO B inhibitors in anti-Parkinsonian therapy

M. Sandier. V. Glover, J. Willoughby and C. Gibb 883

Teaching and research in pharmacology andtoxicology in developing countries

Teaching of pharmacology under economic stress: The Nigerian experienceH.O. Obianwu 889

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Teaching clinical pharmacology in developing countriesH. Fraser 895

New teaching technology: A solution to increasing financial restraintsB. Furman 899

Where staff and students rarely meet: The open universityW. Perry 903

Research and development in toxicology and pharmacology in developingcountries. Problems, priorities and possible solutions

J.A. Castro 907Drugs, needs and regulation

/. Darmansjah 911Risk benefit analysis for pesticide use in developing nations

I.C Munro and K.R. Solomon 915Ethnopharmacology and development of new therapeutic agents

Gan-Zhong Liu 927

Index of authors 931Subject index 937