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Il Farmaco 55 (2000) 414–421

Erratum

Erratum to: ‘‘Receptor chemistry towards the third millennium’’�

[Farmaco 55 (2000) 69–75]

Piero Angeli a, David J. Triggle b

a Department of Chemical Sciences, Uni6ersity of Camerino, Camerino, Italyb Office of the Pro6ost, State Uni6ersity of New York, Buffalo, NY, USA

The publisher sincerely regrets that the above article had incorrect running headlines and accepts full responsibilityfor this error. The corrected article is published in its entirety on the following pages.

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Il Farmaco 55 (2000) 415–421

Meeting Report

Receptor chemistry towards the third millennium�,��

12th Camerino–Noordwijkerhout Symposium held inCamerino (MC), Italy, September 5–9, 1999

The series of Camerino Symposia present the mostrecent knowledge and discoveries in the growing field ofdrug–receptor interaction and the design and mecha-nisms of drug action. ‘‘Receptors in Neurodegenerati6eDiseases ’’ was the general subject of this ‘‘End-of-Mil-lennium meeting ’’ chaired by Mario Giannella (Univer-sity of Camerino, Italy). Specifically, the meetingfocused on the involvement of cholinergic and adrener-gic receptors in neurodegenerative and cardiovasculardiseases, respectively, and also provided an update onsigma-, imidazoline-, excitatory amino acid-,chemokine-, kappa opiod-, ICAM-1-, and neuro-trophin-receptors. Almost 200 participants in an inter-national audience, composed principally of chemists,biochemists and pharmacologists, spent the five days ofthe conference in the eye-catching medieval setting ofthe University of Camerino and enjoyed both the scien-tific and cultural programs. Despite some residual dam-age from the earthquake of 1997, the town again put itsbest face forward for a very successful meeting.

1. Introduction

The well-balanced interdisciplinary cooperationamong chemists, biochemists, pharmacologists, bio-physicists and physiologists continues to be the mainfeature and the driving force of this symposium whichis, in fact, a continuation of a series started in 1978 andfrom 1987 run jointly as the Camerino–Noordwijker-hout series alternating every 2 years between Camerinoand Noordwijkerhout (The Netherlands). The 1999 edi-tion was attended by close to 200 participants, from

industry and academia, from 19 countries, who listenedto 40 speakers.

2. Cholinergic receptors and neurodegenerative diseases

Fulvio Gualtieri (University of Florence, Italy)chaired this first session dedicated to the cholinergicapproach for the treatment of dementias and particu-larly of Alzheimer’s disease (AD). Currently availabledrugs are not particularly effective — tacrine,donezepil and rivastigmine —when directed againstcholinesterase or muscarinic receptors. Amyloid b pep-tides derive from abnormal proteolytic processing ofamyloid precursor protein (APP) and represent highlyhydrophobic and self-aggregating molecules suspectedof being the main determinant of the disease. Since thestimulation of muscarinic M1 receptors can acceleratethe a-secretase cleavage of APP, the efforts of manyresearchers have been directed towards developing com-pounds able to increase the level of cholinergic trans-mission in the brain directly (nicotinic and M1 selectivemuscarinic agonists) or indirectly (acetylcholinesteraseinhibitors, M2 selective muscarinic antagonists, acetyl-choline releasers, high-affinity choline uptake in-hibitors). The potential of centrally acting nicotinicagonists has been recognized for the treatment ofParkinson’s disease (PD) as well, because of their abil-ity to release other neurotransmitters like dopamine.

2.1. Nicotinic receptors

CNS nicotinic mechanisms in normal human cogni-tive and behavioral functioning as well as their role indisease states, including AD, PD, schizophrenia andTourette’s disorder, were discussed by Paul Newhouse(University of Vermont, College of Medicine, Burling-ton, VT, USA). Nicotinic receptors are involved in thecontrol of ACh, DA and NE release as well as thecontrol of NGF release — all involved in memoryfunctions and neuronal growth and development, re-spectively. A positive association has been described

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P. Angeli, D.J. Triggle / Il Farmaco 55 (2000) 415–421416

between smoking and the incidence of AD and themoderation of schizophrenia. The nicotinic receptor is aligand-gated ion channel and the a4b2-type is of partic-ular importance in the CNS. Recent studies withnicotine and novel nicotinic agonists such as ABT-418in AD patients suggest that nicotinic stimulation canimprove the acquisition and retention of verbal infor-mation and decrease errors. Acute administration andstimulation of nicotine and the novel nicotinic agonistSIB-1508 improve some aspects of cognitive and motorperformance and may improve the processing speed ofmore complex tasks.

An overview by Richard Glennon (School of Phar-macy of Virginia Commonwealth University, VA,USA) focused on the structure–activity relationships(SARs) formulated in pharmacophores [Beers and Re-ich, Nature 225 (1970) 917; Sheridan et al., J. Med.Chem. 29 (1986) 899] for the binding of nicotinic agentsat, primarily, a4b2-type nicotinic receptors. The affinityvalues of many nicotinoids (compounds displaying astructural similarity to nicotine in that they contain abasic nitrogen atom and a pyridine, or equivalent,aromatic ring) and miscellaneous agents, for the a4b2

population of nicotinic acetylcholine receptors(nAChRs), were presented and related to the nicotinestructure. Limitations to these early pharmacophoremodels were presented. Glennon also presented ligandsactive on a7 nAChRs, a neuronal population character-ized by high affinity for a-bungarotoxin and reducedaffinity for nicotine.

Structural aspects of high-affinity ligands for the a4b2

neuronal nicotinic receptor was the subject dealt withby Michael J. Dart (Abbott Laboratories, Abbott Park,IL, USA). On the theme of pharmacophores Dartnoted that the compounds having low-energy confor-mations that achieve the best-fit superposition with theputative pharmacophoric elements of (− )-epibatidinealso exhibit the highest binding affinity for the a4b2

receptor. He observed that the receptor exists in multi-ple allosteric states and that ligand binding assays,reflecting principally the desensitized state may notmirror functional status. He observed that nicotine andepibatidine have served as structural templates for thedesign of the majority of active compounds and that allpotent a4b2 ligands include a basic or quaternized nitro-gen atom and a less basic nitrogen or a carbonyloxygen interacting with electron rich and electron defi-cient sites on the receptor, respectively. Among theligand classes retaining potent a4b2 receptor bindingaffinity, the pyrrolizidine, 2-azabicyclo[2:2:1]heptaneand furo[2-3-b ]pyridine nuclei serve as useful designtemplates. ABT-594, a member of a novel series of3-pyridyl ether compounds, possesses broad-spectrumantinociceptive activity in preclinical models and is thefirst nAChR-mediated analgesic to enter human clinicaltrials.

Nicholas D.P. Cosford (SIBIA Neurosciences Inc.,La Jolla, CA, USA) outlined the SIBIA approach ofscreening in cell lines with a fluorescence-based assayand discussed altinicline (SIB-1508Y), a selectivenAChR agonist that was discovered by employing amedicinal chemistry approach based on modifying thestructure of nicotine. This small molecule, designed toselectively activate neuronal nAChRs, is in Phase IIclinical trials for PD where it has shown neuroprotec-tive properties in animal models. Biological data forcognitive deficits and antidepressant properties werealso presented.

M. Rosini (University of Bologna, Italy) discussedthe polymethyleneamine ‘universal template’ [Bolognesiet al., J. Med. Chem. 41 (1998) 4150], which appears inmolecules active at multiple receptor types includingmuscarinic, adrenergic, opiod and others. Methoc-tramine is the parent member of the series and thisstructure was combined with the non-competitive phi-lanthotoxin-343 to obtain new molecules.

2.2. Muscarinic receptors

In an introductory review the session Chair, PieroAngeli (University of Camerino, Italy), discussed themuscarinic receptor classification, m1–m5 and M1–M5,and the ligands available and the extent of receptordiscrimination provided by them.

William S. Messer (College of Pharmacy, The Uni-versity of Toledo, Toledo, OH, USA) and Haile Tecle(Parke-Davis Pharmaceutical Research Division ofWarner-Lambert Company, Ann Arbor, MI, USA)presented their results on selective M1 muscarinic ago-nists useful for the treatment of AD. Messer presentedCDD-0102 (a 1,4,5,6-tetrahydropyrimidine with anoxadiazole substituent) and xanomeline, two agoniststhat can reverse memory deficits associated with a lossof basal forebrain cholinergic function. CDD-0102 andxanomeline are both functionally selective for M1 re-ceptors. CDD-0102 is considered a candidate for clini-cal trial. Messer discussed a bivalent ligand approachfor developing more selective muscarinic agonists inwhich two xanomeline molecules were linked by aflexible chain of varying lengths and maintained activ-ity. Zang and Wess [J. Biol. Chem. 274 (1999) 19487]have reported dimeric muscarinic receptors.

A series of 1-azabicyclo[2.2.1]heptane-3-one oximesare potent muscarinic agonists whose SAR studies wereoutlined by Tecle. He argued that ‘larger’ agonists wereneeded in order to provide better receptor subtypediscrimination. CI-1017 improved spatial memory inhippocampal deficient mice and nbM-lesioned rats andmarkedly increased the soluble form of APP and de-creased the production of amyloidogenic Ab. CI-1017was found to be well tolerated in Phase I clinical trialsand is proceeding into Phase II studies.

P. Angeli, D.J. Triggle / Il Farmaco 55 (2000) 415–421 417

The idea that drugs acting at allosteric sites of themuscarinic receptor might achieve the selectivity thusfar not realized at the agonist site has long been attrac-tive, although unproven. Ligands for the allosteric siteof ACh M2 receptors are able to retard the dissociationof simultaneously bound ligands for the orthosteric site.Ulrike Holzgrabe (University of Wurzburg, Germany)optimized the affinity of the modulators for the com-mon allosteric binding site of muscarinic M2 receptors,taking the phthalimido substituted alkane–bisammo-nium compound W 84 as a starting point. With 3DQSAR analysis, Holzgrabe presented highly potentcompounds characterized by a rigid hydrophobic moi-ety in position 3 of the phthalimide and a large aro-matic area annellated to the imide. The perspective tofind ligands endowed with higher allosteric potency andsuitable for therapeutic purposes may be closer. Al-losteric modulators of muscarinic M2 receptors werepresented by D.P. Zlotos (University of Wurzburg,Germany; poster presentation) as bisquaternarycaracurine V derivatives: depending upon the sub-stituents affinities varied from 3 to 1750 nM as al-losteric modulators.

New analogues of McN-A-343 were reported by C.Keim (University of Frankfurt, Germany; poster pre-sentation). Very potent compounds were obtained witha phenyl substituent in the side chain and 4-F in placeof 3-Cl (pKI values of 9.40–8.60 against M1-M5), butno real evidence of selectivity. The 2,2-diphenyl-1,3-dioxolane-4-trimethylammonium structure wasmodified to add N-alkyl substituents of chain lengthn=2–5 (P. Angeli et al., University of Camerino, Italy;poster presentation). Varying degrees of receptor selec-tivity were obtained according to n and the N-alkylsubstituents: when n=1 and R and R%=Et, M1 andM2 selective; when n=4 and R and R%=Me, M3

selective.

3. Receptors in cardiovascular diseases

3.1. Adrenergic receptors

Amedeo Leonardi (Pharmaceutical R&D Division,Recordati S.p.A., Milan, Italy), charged Chair of thissession, could not be present because of illness.

J. Paul Hieble (SmithKline Beecham Pharmaceuti-cals, King of Prussia, PA, USA) presented a compre-hensive analysis of adrenoceptor (AR) classificationand of the drugs that interact with these receptors.Emphasis was given to the therapeutic role of eachsubtype, notably hypertension, benign prostatic hyper-plasia (BPH), congestive heart failure, cardiac arrhyth-mia. Among the a1 antagonists, prazosin congenersdoxazosin and terazosin remain important options inthe treatment regimen available for hypertension, while

the cardiovascular profile of the selective a1B antago-nists (+ )cyclazosin and L-765,314 has not been exten-sively characterized. Selective a1 antagonists, such asRS 17053, Rec. 15/2739, SL 890591 and the mostrecently introduced tamsulosin, have been proven to beeffective drugs for BPH. Potential targets for an a2-an-tagonist include hypertension, obesity, non-insulin-de-pendent diabetes and erectile dysfunction. BRL 48962is, at the moment, the only antagonist endowed withsignificant a2A selectivity. a1 Agonists may be useful toincrease the tone of the urethral sphincter as therapyfor stress incontinence, without an associated increasein systemic blood pressure. NS-49, an a1 agonist havingthis selectivity profile, is currently in clinical trials forstress incontinence. b3 Agonists, such as BRL 37144,have been evaluated in man as potential anti-obesityand anti-diabetic drugs. The difficulty in extendinguseful agents in this area from rodent to human phar-macology was noted: BRL 37344 is selective at b3

rodent receptors but is not efficacious in man. Mostdrugs act at a single receptor type, but carvedilol, anantagonist with high affinity for all nine AR subtypes,has found clinical use in the treatment of congestiveheart failure. It is possible that a1 and b AR antagonistactions of carvedilol are synergistic in the therapy ofheart failure patients. The existence of a b4 receptor wasspeculated upon and may drive a cardiac inotropicresponse that might be helpful in acute congestive heartfailure.

Susanna Cotecchia (University of Lausanne, Switzer-land) presented the results of her studies combining 3Dmodel building of the receptor structure with computa-tional simulation of receptor dynamics on the activa-tion process of the a1a and a1b adrenergic receptorsubtypes as well as on the mechanisms of action ofdrugs acting at these receptors. Specific mutations thatproduced constitutively active mutants were discussed:in the a1b receptor mutation of residue A293 produceda range of active receptors. A model was advanced thatsuggests that receptor switching maybe similar. Amodel was presented in which R143 lies in a polarpocket comprising N63, D91, N344, Y348 and T295.Protonation of D142 is linked to receptor activation bytriggering the shift of R143 out of its pocket. The use ofconstitutively active receptors permitted analysis of an-tagonist ligands. N-arylpiperazines as alpha-blockerswere identified that display the most striking differenceat the two a1 subtypes, being inverse agonists withnegative efficacy at the a1b type but not at the a1a type.In particular, REC 15/3039, REC 15/2739 and REC15/3011 are the first alpha-blockers identified so farwhich do not display inverse agonism at one of the a1

subtypes, namely the a1a. Preliminary SAR studies sug-gest that the geometry of the protonated nitrogen atomas well as that of the molecular moiety closest to thisnitrogen might be responsible for the functional effectof the ligands tested.

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Recent developments in the design of new a1-ARantagonists bearing a quinazoline or a benzodioxanemoiety were discussed by Carlo Melchiorre (Universityof Bologna, Italy). Structural modifications, such asreplacement of the piperazine ring with a linear chainand of the furan ring with a phenyl unit, on prazosin-related compounds were summarized. In particular, thepresence of a phenyl ring offered the opportunity tostudy the effect of different substituents in the receptorrecognition process. Here a 2-MeO substituent or a2-CF3 substituent yielded a1a and a1d selective com-pounds, respectively [Giardina et al., J. Med. Chem. 39(1996) 4602]. Moreover, structural modifications per-formed on WB 4101-related compounds have beenanalyzed [Quaglia et al., J. Med. Chem. 42 (1999) 2961].A trans-phenyl ring at C3 of the 1,4-benzodioxan main-tained alpha-antagonist activity, but decreased activityat 5HT1a and a2 receptors. It has been shown that thereplacement of the carbon chain separating the amineand the phenoxy groups of WB 4101 with a cyclopen-tane ring afforded stereoisomers that retained goodaffinity for a1D-ARs or 5-HT1A receptors according tothe configuration of the cyclopentane unit.

Positron emission tomography (PET) is an imagingtechnique that provides the possibility to assess humancardiac ARs directly in vivo with the help of effectiveradioligands for the targeted ARs. Changes in thenumbers of human ARs are associated with diseases,such as myocardial ischemia, congestive heart failure,cardiomyopathy and hypertension. Victor W. Pike(Hammersmith Hospital, London, UK) focussed on thestatus of AR radioligand development in the context ofthe imaging capabilities of PET. Several fundamentalcriteria, such as high affinity and selectivity for thetarget receptor population, antagonist action, stereose-lectivity where enantiomers exist, low or moderatelipophilicity, low metabolism and toxicity, amenabilityto labeling with a positron-emitter (generally 11C or18F), must be observed by a prospective radioligand tobe effective for PET imaging of receptors in vivo.Among b-AR radioligands, [11C]pindolol, [11C](S)-cara-zolol and mainly [11C](S)-CGP 12177 and [11C](S)-CGP12388 would be excellent radioligands for PET imaging,while [18F](S)-1%-fluorocarazolol is a promising radioli-gand for imaging pulmonary and brain b-ARs. The useof PET to investigate the a-adrenergic system is of greatinterest, since in vitro evidence suggest that a1-ARslevels alter because of myocardial ischemia. In thisrespect, [11C]GB67, a potent and selective a1-AR antag-onist, appears as a promising radioligand for the studyof a1-ARs in human subjects and in normal malevolunteers revealed a high and sustained uptake ofradioactivity in myocardium giving a clear image of theleft ventricular wall and septum.

4. Enigmatic receptors

4.1. Sigma and imidazoline receptors

An overview of the imidazoline (I) and sigma (s)receptors was presented by Livio Brasili (University ofModena, Italy), focussing on the imidazoline and sigmareceptors, sites still awaiting a clear-cut definition ofphysiological function and selective ligand action. Atleast three imidazoline-preferring sites exist of which I1

and I2 are associated with membrane and mitochon-drial locations, respectively, and characterized by highaffinity for both clonidine and idazoxan and for ida-zoxan alone. Endogenous ligands have been proposed,including ‘clonidine-displacing substance’ and agmatine(decarboxylated arginine). These sites await selectiveligands as possible therapeutic agents in the treatmentof a variety of disorders such as hypertension, diabetesmellitus, depression and stroke: new agents such asPMS 812, 2-BFI, BU-224, BU-239, tracizoline andbenazoline are emerging.

Three sites (s1, s2 and s3) seem to define sigma (s)receptors that play a modulatory role in the centralnervous system. The search for selective s receptorantagonists, which may be effective antipsychoticdrugs, is producing specific compounds, such as NE100 (s1/s2=55) an antipsychotic drug which is inPhase II clinical trials, and spipethiane, one of the mosts1-selective ligands (s1/s2=832). The s1 receptor hassome 30% homology to the C8-C7 isomerase of thesterol biosynthetic pathway.

The involvement of non-ARs in the induction of thehypotensive effect of imidazoline-related drugs was re-viewed by Pascal Bousquet (Louis Pasteur University,Strasbourg, France). Recently, a synthetic imidazolineligand, benazoline, which is 10 421 times more selectivefor IRs than for a2-ARs (A2Rs), has become available.LNP 509 is an imidazoline derivative selective for IRs,while S23515 exhibits high affinity for I1Rs, with aselectivity ratio (I1 over A2Rs) over 4000. Finally, ril-menidine, an imidazoline-like oxazoline, has beendefined as the first centrally acting antihypertensivedrug selective for IRs. These results provide evidencethat a drug highly selective for I1Rs over A2Rs canreduce blood pressure, and actions on I1Rs and A2Rsmay potentiate each other through an interaction be-tween themselves. This seems to account for themarked and rapid hypotensive effect caused by hybriddrugs, such as clonidine.

M. Massi (University of Camerino, Italy) discussedthe possible role of I2 receptors in hyperphagia. Thereappears to be a peripheral site at which imidazoline I2

ligands influence feeding, but since idazoxan also in-duces feeding the role of an alpha-AR is not to bediscounted.

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Sigma receptors have important functions in brainand outside of the nervous system, and subserve a moregeneral role than a neurotransmitter receptor. Sigma-1and sigma-2 constitute two subclasses that are differen-tiable by pharmacological profile, function, and molec-ular size, both having high to moderate affinity fortypical neuroleptics, with haloperidol exhibiting highestaffinity for both sites. Wayne D. Bowen (NationalInstitutes of Health, Bethesda, MD, USA) focused hisattention particularly on the possible role of sigma-2receptors in regulation of cell proliferation and mainte-nance of cell viability. This author presented his resultsshowing that sigma ligands cause damage to cell pro-cesses and ultimate death by an apoptotic mechanismwith concomitant changes in intracellular calcium andin cell morphology. On the therapeutic point of viewsigma-2 receptor antagonists my be useful tools forameliorating the debilitating effects of tardive dyskine-sia resulting from chronic treatment of psychoses;sigma-2 receptor agonists could be useful alone asantineoplastic agents at doses which induce apoptosisor, at subtoxic doses, in combination with commonantineoplastic agents to reverse drug resistance. Finally,activation of sigma-2 receptors could have chemosensi-tizing effects (potentiation of doxorubicin actions) andsigma receptor ligands may be useful for non-invasivetumor imaging.

5. Excitatory aminoacid receptors

Glutamate receptor systems were reviewed by Gio-vanni Gaviraghi (Glaxo Wellcome SpA, Verona, Italy).They remain a major target for neurodegenerative andrelated disorders although success has yet to appearclinically. Two main types of glutamate receptors havebeen identified: three inotropic receptors, that is N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate,and eight metabotropic glutamate G protein-coupledreceptors designated as mGluR1–mGluR8. Their struc-ture and functions and their subtypes have been charac-terized as well as their involvement in human diseases.The ionotropic NMDA receptor subtype has been asso-ciated with the neuronal damage induced by acuteischemia in stroke, while AMPA and mGluR2 subtypesto epileptic episodes. The amino acid glycine acts as acoagonist with glutamate of the NMDA receptor.

David G. Trist (Glaxo Wellcome SpA, Verona, Italy)related on the identification of the glutamate receptorsubtypes. Changes in glutamate transmission have beenassociated with a number of CNS pathologies. Compet-itive glycine antagonists, such as GV150526, are neuro-protective and seem to have less side-effects than otherapproaches to block the NMDA receptor such asNMDA antagonists (CCP) or NMDA ion channel

blockers (MK-801). In the MCAO model it reduced thespread of damage and it was reported to have promis-ing physical and behavioral protective effects in a small(n=6) IIA trial. A Phase III trial is now under way.Moreover, glycine antagonists such as GV196771 blockhyperalgesia and allodynia in animal models of pain.

Roberto Pellicciari (University of Perugia, Italy) pre-sented novel metabotropic glutamate receptor ligandsable to disrupt the chain of events linked to neurode-generation without impairing excitatory neurotransmis-sion. Ligands for the glycine co-receptor site continueto be of interest as therapeutic agents. Daniele Donati(Glaxo Wellcome SpA, Verona, Italy) presented glycineantagonists with indole-2-carboxylate and ben-zazepinone structures. The indole derivative GV 228869had a KI value of 2 nM and was used as a pharma-cophoric lead to the benzazepinone GV 224029 thathad similar in vivo activity to GV 150526 now in PhaseIII clinical trial.

6. Receptors for neurodegenerative disorders

6.1. Neurotrophic factor receptors

Wolfgang Froestl (Novartis Pharma AG, Basel,Switzerland) discussed the use of trophic factors —NGF, BDNF, CNTF, GDNF — in the treatment ofneurodegeneration associated with human diseaseswhich is accounted for by their ability to regulatedevelopmental neuronal survival and adult nervous sys-tem plasticity. The findings that nerve growth factor(NGF) prevents cholinergic neuron atrophy and ame-liorates spatial memory impairment in rats led to theidentification of molecules that induce the synthesis ofNGF and potentiate its actions, such as the 5-HT1A

receptor agonist SR-57746A (Sanofi) which is in Phase3 clinical trials, the hypoxanthine AIT-082 (Neothera-peutics), which is in Phase II, and GPI-1046 (Guild-ford). Froestl also noted the ‘death receptors’ —TNFR1, Fas/CD95, TRAMP, TRAIL1/2 and p75NTR — activation of which leads to apoptosis.

Moses V. Chao (New York University School ofMedicine, New York, NY, USA) outlined the controlof cell survival and death by the NGF family as deter-mined by the Trk receptor tyrosine kinase and the p75neurotrophin receptor. These may be loosely associatedand may function to bidirectionally control survivaland death. p75 is upregulated in stress injury (a ‘stress’receptor?) and the association of a death regulator witha growth factor may be important for correcting ‘wiringwhen cells are exposed to the wrong factor’.

Mark W. Sleeman (Regeneron Pharmaceuticals Inc.,Tarrytown, NY, USA) focussed on CNTF and itsreceptor (CNTFRa). This receptor anchors via glyco-syl/PI linkage and with other proteins gp130 and

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LIFRbeta homodimerizes. A clinical trial of CNTFagainst motorneuropathy failed, but a decreased ap-petite was noted. Axokine, a second-generation CNTF,is in trial for obesity. In ob/ob mice it blocks the weightrise and decreases body fat with little impact on leanbody mass. This is a centrally mediated effect, probablymediated in the hypothalamus.

Remi Quirion (McGill University, Montreal, Quebec,Canada) illustrated the role of insulin-like growth fac-tors I and II (IGF-I and IGF-II), that is their trophic aswell as neuromodulatory functions in the brain. Theeffects of IGF-I on key markers of the AD brainsnamely cholinergic dysfunction, neuronal amyloid toxi-city, tau phosphorylation and glucose metabolism sug-gest the potential usefulness of this growth factor in thetreatment of neurodegenerative diseases. Moreover, therecent development of a small, non-peptidyl mimetic ofinsulin, L-783,281, able to directly activate the insulinreceptor, suggests that a similar strategy could be usedfor IGF-I and the IGF-I receptor leading to the charac-terization of IGF-I mimics of potential clinicalusefulness.

Death receptors and apoptosis were presented byPascal Schneider (University of Lausanne, Switzerland).These receptors are members of the TNF family andhave a specific intracellular domain that recruits otherproteins, notably TRADD, FADD and the proteaseCaspase-8. Apoptosis, programmed cell death, is aphysiologic event that helps to keep the right number ofcells in the organism. This process is also a favoredresponse in cells exposed to stress stimuli and damagingconditions, preventing the appearance and proliferationof potentially dangerous cells. Deregulation of theapoptotic process leading to either increased or reducedcell death, in fact, can contribute to various pathologicconditions such as autoimmune diseases, AIDS or can-cer. Decoy receptors also exist that are homologs ofdeath receptors, but lack the death domain: these in-clude TRAIL-R3 and FLIP.

7. Hijacked receptors

David J. Triggle (State University of New York,Buffalo, NY, USA), who chaired the hijacked receptorsession, gave some examples of receptors recognized bynon-related ligands, such as the rabies virus at n-AChR4, the CD4 and chemokine receptors for HIV,the fibroblast growth factor receptor for herpes sim-plex, ICAM-1 for the rhinovirus, EGF receptors forSalmonella typhimurim and alpha-dystroglycan for My-cobacterium leprae. The use of the CFTR by S. typhiiand the failure to infect cells expressing a nonfunctionalCFTR was noted, together with the resistance to infec-tivity of individuals expressing mutant chemokinereceptors.

Jordi Bella (University of Manchester, UK) discussedthe interaction between human rhinoviruses (HRVs)and their receptor, intercellular adhesion molecule-1(ICAM-1). Molecular models resulting from the combi-nation of crystal structures of HRVs and ICAM-1fragments with electron microscopy reconstructions ofthe complexes, have been useful to understand receptorrecognition, binding specificity and mechanisms bywhich ICAM-1 induces virus uncoating.

Viral-encoded GPCRs may play an important role inviral infection and are likely implicated in chronicdiseases. Martine J. Smit (Vrije University of Amster-dam, The Netherlands) underlined the role of GPCRsas successful drug targets in the past and as emergingtargets for the development of drug research. A numberof viruses, including HCMV, HHV6-8, pappiloma virusetc., contain ‘hijacked’ genes for GPCRs. HHV-8GPCR is likely related to the Kaposi sarcoma, is linkedto angiogenesis and is constitutively active. CMV con-tains four GPCRs and may be linked to atherogenesis.The challenge is the design of small molecule drugs.

Silvano Sozzani (Mario Negri Institute, Milano,Italy) continued the discussion of viral-encodedchemokines and discussed the therapeutic potential ofanti-chemokines. He observed that mammalian virusescould avoid immune surveillance by expressingchemokines and chemokine receptors [Sozzani et al.,Blood 92 (1998) 4036]. HSV 8 encodes chemokineshomologous to the MIP CC chemokines that may serveas endogenous antagonists.

8. General topics and discussion

Henk Timmerman (Vrije University of Amsterdam,The Netherlands) provided an overview of current con-cepts in understanding.

Roberto Maggio (University of Pisa, Italy) intro-duced the concept of (hetero/homo)dimers in GPCR.Although receptors are generally considered as closelypacked structures, actually they can behave structurallyin a fashion analogous to multiple subunit receptors.New functional structures, as a dimer, are formed fromthe combination of truncated muscarinic receptors. Thecombination of m2 ‘truncated’+m3 ‘tail’ to give recep-tors that both bind ligands and express functionalactivity was discussed. Additionally, hybrids of adrener-gic and muscarinic receptors exist, which can be formedby these subunit receptor interactions. When differentsubtypes of muscarinic receptors are co-expressed in thesame cells, they might interact to form heterodimerswith new pharmacological properties. Although themolecular mechanism that underlies dimerization is notknown, a domain swapping in GPCR dimerization hasbeen recently proposed. This may be the mechanism bywhich M2 and M3 muscarinic receptors interact in theirheterodimerization acquiring novel functions.

P. Angeli, D.J. Triggle / Il Farmaco 55 (2000) 415–421 421

Rob Leurs (Vrije University of Amsterdam, TheNetherlands) discussed constitutively active GPCRsstarting from original observations on the opiate recep-tor [Costa and Herz, Proc. Natl. Acad. Sci. USA 86(1989) 7321] and the concept of agonists, inverse ago-nist and antagonists. Using examples from the H1 andH2 receptor systems, he argued that most ‘conventional’antagonists might, in fact, be inverse agonists. A num-ber of disease states are likely to involve constitutivelyactive GPCRs and inverse agonists should have a ther-apeutic role in treating such disorders resulting fromincreased expression, mutations or autoantibodies).

A novel G protein, Gb5 isoform, has been presentedby William F. Simonds (NIDDKD, Bethesda, MD,USA). This subunit exhibits novel properties in itsactivation of effector pathways such as MAPK, phos-pholipase C-b, and adenylyl cyclase type II when com-pared with Gb1. A highly specialized role for Gb5 in Gprotein signal transduction is indicated.

John L. Neumeyer (Harvard Medical School,McLean Hospital, Belmont, MA, USA) showed a seriesof morphinans, structural analogs of cyclorphan, ketomorphinans and a keto benzomorphan, structurallyrelated to ketocyclazocine, as kappa opioid agonistsuseful in the treatment of cocaine dependence. In fact,activation of kappa opioid receptors may functionallyantagonize some effects of cocaine, possibly by inhibit-ing the release of dopamine from dopaminergic neu-rons, and may provide a new approach to thecontinuing search for effective treatment medications.The binding results showed that two morphinans,namely MCL-101 and (− )cyclorphan, had a highaffinity for m, d and k opioid receptors. In particular,while both are k agonists, only (− )cyclorphan pro-duces some antinociception mediated by the d opioidreceptor. While having similar affinity for the m opioid

receptor, (− )cyclorphan and MCL-101 display oppos-ing effects at the m receptor, the former behaving as a mantagonist, the latter as a m agonist.

The symposium concluded with an overview byDavid J. Triggle (State University of New York atBuffalo, Buffalo, NY) on the future of medicinal chem-istry. He argued that medicinal chemistry, and thepharmaceutical sciences in general, would be shaped byboth scientific and economic factors. The paradigms ofmolecular biology applied to molecules — diversity,reproduction, evolution, targeting and delivery —would become components of synthetic chemistry and,in a flight of fancy, it was proposed that ‘circulatingnanofactories’ might be envisaged that contained thesynthetic machinery and targeting processes necessaryto maintain pharmaceutical vigilance over the body. Itwas noted that science alone would not be the onlyfactor determining the future of the pharmaceuticalsciences. Economic, political and social issues wouldalso be of critical importance. Notably, the cost of drugdevelopment would necessitate the adoption of newcost-reducing measures, as would the social demandsfor increased access to healthcare and the politicaldemands for cost-reduction.

Piero AngeliDepartment of Chemical Sciences,

Uni6ersity of Camerino,Camerino,

Italy

David J. TriggleOffice of the Pro6ost,

State Uni6ersity of New York,Buffalo,

NY, USA