the invention will now be described by way of reference only to the following general methods and experimental examples , and to the figures . abbreviations used herein are as follows : throughout the specification conventional single - letter and three - letter codes are used to represent amino acids . protected amino acids and resins were obtained from novabiochem . tfa , dipea and dmf ( peptide synthesis grade ) were purchased from auspep . all other materials were reagent grade unless otherwise stated . preparative scale reverse - phase hplc separations were performed on a vydac c18 reverse - phase column ( 2 . 2 × 25 cm ), and analytical reverse - phase hplc separations were performed on a waters delta - pak preppak c18 reverse - phase column ( 0 . 8 × 10 cm ), using gradient mixtures of solvent a = water / 0 . 1 % tfa and solvent b = water 10 %/ acetonitrile 90 %, 0 . 09 % tfa . the molecular weight of the peptides was determined by electrospray mass spectrometry recorded on a triple quadrupole mass spectrometer ( pe sciex api iii ), as described elsewhere ( haviland et al , 1995 ). 1 h - nmr spectra were recorded on either a bruker arx 500 mhz or a varian unity 400 spectrometer . proton assignments were determined by 2d nmr experiments ( dfcosy , tocsy , noesy ). non - peptidic compounds were synthesized using conventional organic chemical methods . compounds were analysed by 1 h - nmr spectroscopy and by mass spectrometry . some representative peptide syntheses are now given . linear peptide sequences were assembled by manual step - wise solid - phase peptide synthesis with hbtu activation and diea in situ neutralisation . boc chemistry was employed for temporary n α - protection of amino acids with two 1 min treatments with tfa for boc group removal . the peptides were fully deprotected and cleaved by treatment with liquid hf ( 10 ml ; p - cresol ( 1 ml ); − 5 ° c . ; 1 - 2 hr ). analytical hplc ( gradient ; 0 % b to 50 % b over 40 min ): 7 , rt = 32 . 0 min , [ m + h ] + ( calc . )= 900 . 5 , [ m + h ] + ( exper . )= 900 . 7 ; 8 , rt = 32 . 2 min , [ m + h ] + ( calc . )= 899 . 6 , [ m + h ] + ( exper . )= 899 . 7 ; 9 , rt = 30 . 0 min , [ m + h ) + ( calc . )= 900 . 5 , [ m + h ] + ( exper . )= 900 . 7 ; 10 , rt = 23 . 8 min , [ m + h ] + ( calc . )= 860 . 5 , [ m + h ] + ( exper .) 860 . 5 . this is a general method used for the synthesis of a wide range of cyclic antagonists covered by this patent . for example , in the case of cycle 11 , its linear precursor peptide was synthesised by fmoc chemistry using hbtu / diea activation on an fmoc - d - arg ( mtr )- wang resin . fmoc group removal was effected using two 1 min treatments with 50 % piperidine / dmf . cleavage and deprotection using 95 % tfa / 2 . 5 % tips / 2 . 5 % h 2 o gave the mtr - protected peptide , which was purified by rp - hplc . cyclization of the protected , purified peptide using 3eq bop and 10eq diea at a 1 mm concentration in dmf stirring for 15 hr gave the cyclised product , which was fully deprotected using 1m tmsbr in tfa . a final rp - hplc purification gave the desired peptide in yields of 50 % for the cyclisation . rt = 37 . 7 min , [ m + h ] + ( calc .) 910 . 5 , [ m + h ] + ( exper . )= 910 . 7 . cyclization of the cleaved and fully deprotected peptide was achieved by stirring a 1 mm solution in dmf with 3eq bop and 10 eq pyridine as base for 15 hr . a final rp - hplc purification gave the desired peptide in yields of 22 % for the cyclization . rt = 37 . 3 min , ( m + h ]+( calc . )= 896 . 5 , [ m + h ]+( exper . )= 896 . 5 . 1 h - nmr spectra were recorded for compound 7 ( 3 mg in 750 μl d 6 - dmso , δ2 . 50 ) referenced to solvent on a varian unity 400 spectrometer at 24 ° c . two dimensional 1 h - nmr noesy ( relaxation delay 2 . 0 s , mix time 50 - 300 ms ), dfq - cosy and tocsy ( mixing time 75 ms ) experiments were acquired and recorded in phase sensitive mode . acquisition times = 0 . 186 s , spectral width = 5500 hz , number of complex points ( t 1 dimension )= 1024 for all experiments . data was zero - filled and fourier transformed to 1024 real points in both dimensions . nmr data was processed using triad software ( tripos assoc .) on a silicon graphics indy work station . 2d noe cross peaks were integrated and characterised into strong ( 1 . 8 - 2 . 5 å ), medium ( 2 . 3 - 3 . 5 å ) and weak ( 3 . 3 - 5 . 0 å ). preliminary three - dimensional structures were calculated from upper and lower distance limit files using diana 2 . 8 ( 69 distance constraints , including 27 for adjacent residues and 6 further away ) with the redundant dihedral angle constraints ( redac ) strategy . upper and lower distance constraints were accurately calculated using mardigras . at this stage the peptide was examined for possible hydrogen bonds , and these were added as distance constraints . the 50 lowest energy diana structures were subjected to restrained molecular dynamics ( rmd ) and energy minimisation ( rem ). initially , rem consisted of a 50 step steepest descent followed by 100 step conjugate gradient minimisation . rmd was performed by simulated heating of the structures to 300k for 1 ps , followed by 500k for 1 ps . the temperature was gradually lowered to 300k over 2 ps and finally for 2 ps at 200k . rem was performed again with a 50 step steepest descent , 200 step conjugate gradient followed by a 300 step powell minimisation . the final structures were examined to obtain a mean pairwise rms difference over the backbone heavy atoms ( n , cα and c ). twenty of the 50 structures had a mean rmsd & lt ; 0 . 5 å for all backbone atoms ( o , n , c ). a model of cycle 12 , shown in fig7 was created from the nmr structure of 7 by deleting all nmr constraints , fusing the ornithine side chain amine to the c - terminal carboxylate of d - arg to form an amide , and minimising using powell forcefield ( 1000 iterations ). the modelled structure was then superimposed on the nmr structure with an rmsd 0 . 224 å . assays were performed with fresh human pmns , isolated as previously described ( sanderson et al , 1995 ), using a buffer of 50 mm hepes , 1 mm cacl 2 , 5 mm mgcl 2 , 0 . 5 % bovine serum albumin , 0 . 1 % bacitracin and 100 μm phenylmethylsulfonyl fluoride ( pmsf ). in assays performed at 4 ° c ., buffer , unlabelled human recombinant c5a ( sigma ) or peptide , hunter / bolton labelled 125 , — c5a (˜ 20 pm ) ( new england nuclear , ma ) and pmns ( 0 . 2 × 10 6 ) were added sequentially to a millipore multiscreen assay plate ( hv 0 . 45 ) having a final volume of 200 μl / well . after incubation for 60 min at 4 ° c ., the samples were filtered and the plate washed once with buffer . filters were dried , punched and counted in an lkb gamma counter . non - specific binding was assessed by the inclusion of 1 mm peptide or 100 nm c5a which typically resulted in 10 - 15 % total binding . data was analysed using non - linear regression and statistics with dunnett post test . cells were isolated as previously described ( sanderson et al , 1995 ) and incubated with cytochalasin b ( 5 μg / ml , 15 min , 37 ° c .). hank &# 39 ; s balanced salt solution containing 0 . 15 % gelatin and peptide was added on to a 96 well plate ( total volume 100 μl / well ), followed by 25 μl cells ( 4 × 10 6 / ml ). to assess the capacity of each peptide to antagonise c5a , cells were incubated for 5 min at 37 ° c . with each peptide , followed by addition of c5a ( 100 nm ) and further incubation for 5 min . then 50 μl of sodium phosphate ( 0 . 1m , ph 6 . 8 ) was added to each well , the plate was cooled to room temperature , and 25 μl of a fresh mixture of equal volumes of dimethoxybenzidine ( 5 . 7 mg / ml ) and h 2 o 2 ( 0 . 51 %) was added to each well . the reaction was stopped at 10 min by addition of 2 % sodium azide . absorbances were measured at 450 nm in a bioscan 450 plate reader , corrected for control values ( no peptide ), and analysed by non - linear regression . the following well - known in vivo assay systems may be used to assess the anti - inflammatory activity of compounds of the invention . all assay data are analysed using non - linear regression analysis and student &# 39 ; s t - test , analysis of variance , with p & lt ; 0 . 05 as the threshold level of significance . anaesthetised ( i . p . ketamine & amp ; xylazine ) wistar rats ( 150 - 200 g ) or mice were injected with sterilised air ( 20 ml day 1 , 10 ml day 4 ) into the subcutaneous tissue of the back . the cavity can be used after 6 days , whereupon carrageenan ( 2 ml , 1 % w / w in 0 . 9 % saline ) was injected into the air pouch and exudate was collected after 10 hr . test compounds are administered daily after day 6 and their anti - inflammatory effects assayed by differential counting of cells in the air - pouch exudate . animals were killed at appropriate times after injection and 2 ml 0 . 9 % saline was used to lavage the cavity , lavage fluids were transferred to heparinised tube and cells were counted with a haemocytometer and diff - quik stained cytocentrifuged preparation . alternatively , a routine carrageenan paw oedema was developed in wistar rats by administering a pedal injection of carrageenan to elicit oedema which is visible in 2 h and maximised in 4 h . test compounds are given 40 min before inflammagen and evaluated by microcaliper measurements of paws after 2 & amp ; 4 hr . see fairlie , d . p . et al ( 1987 ). also see walker and whitehouse ( 1978 ). adjuvant arthritis was induced in rats ( 3 strains ) either microbially ( injection of heat - killed mycobacterium tuberculosis ) or chemically ( with pyridine ) by inoculation with the arthritogenic adjuvant co - administered with oily vehicles ( freund &# 39 ; s adjuvants ) in the tail base . ( see whitehouse , m . w ., handbook of animal models for the rheumatic diseases , eds . greenwald , r . a . ; diamond , h . s . ; vol . 1 , pp . 3 - 16 , crc press ). within 13 days the adjuvant arthritis is manifested by local inflammation and ulceration in the tail , gross swelling of all four paws , inflammatory lesions in paws and ears , weight loss and fever . these symptoms , which are similar to those of inflammatory disease in humans ( winter and nuss , 1966 ), can be alleviated by agents such as indomethacin or cyclosporin which also show beneficial effects in man ( eg . ward and cloud , 1966 ). without drug treatment at day 14 , arthritic rats had hypertrophy of the paws , reduced albumin but raised acute phase reaction proteins in serum , and depressed hepatic metabolism of xenobiotics as indicated by prolonged barbiturate - induced sleeping times . to assess activity , compounds were administered for 4 days orally (& lt ; 10 mg / kg / day ) or i . p . from days 10 - 13 following inoculation with arthritogen ( day 0 ). the inflammation was either not visible or very significantly reduced in rear or front paws as assessed by microcaliper measurements of paw thickness and tail volume , as well as by gross inspection of inflammatory lesions . animals are sacrificed by cervical dislocation on day 18 unless arthritis signs are absent , whereupon duration of observations is continued with special permission from the ethics committees . experiments are staggered to maximise throughput and allow early comparisons between compounds . this routine assay is well - accepted as identifying anti - inflammatory agents for use in humans . we have focussed on the c - terminal residues of c5a , in order to explore structure - activity relationships in the search for peptide sequences with potent agonist activity . many of these peptides are full agonists relative to c5a , but have markedly lower potency ( sanderson et al , 1994 , 1995 ; finch et al , 1997 ). our initial structure - activity investigations have been particularly informative . mutating the decapeptide c - terminus of c5a ( seq . id no : 1 , c5a 65 - 74 , ishkdmqlgr ) twice with i 65 y and h 67 f ( eg . 2 ) led to enhancement of agonist potency by about 2 orders of magnitude . these results are summarised in table 2 . analyses of ramachandran plots and 2d nmr spectra for compound 2 suggested that certain structural features , namely a twisted “ helix - like ” backbone conformation for residues 65 - 69 and a β - turn for residues 71 - 74 , might be responsible for activity . these preliminary results provided some insight to structural requirements for tight binding to a c5a receptor . compounds 4 , 5 and 6 in table 2 are the highest affinity small c5a agonists so far known , with up to 25 % c5a potency in human fetal artery , 5 % c5a potency in human pmn enzyme release assays and 1 % c5a affinity for pmn c5ar ( finch et al ., 1997 ). for the pmn receptor , these compounds have up to 100 - fold higher apparent affinity than any small molecule previously described in the literature . the “ high ” affinities ( 70 nm - 6 μm ) of these agonist analogues for c5ar in intact pmn cells have enabled us to identify a common topographical feature in peptide agonists that correlates with expression of spasmogenic activities and enzyme - release assays in human pmns . this preferred backbone conformation is a type ii β - turn . the small size of these agonist peptides makes them amenable to synthetic modification to optimise their affinities , activities , and bioavailabilities , and hence useful as mechanistic probes of receptor activation . we used two dimensional nuclear magnetic resonance spectroscopy to determine the three dimensional structure of 7 and found that while there is no discernible structure in water , there is evidence of a stable gamma - turn structure in dimethylsulfoxide . the 1d 1 h - nmr spectrum of peptide 7 in d 6 - dmso at 24 ° c . shows 4 distinct resonances for amide - nh protons , as summarized in table 3 . to establish their possible involvement in intramolecular hydrogen bonds , a deuterium exchange experiment was performed by adding a 10 - fold excess of d 2 o to the solution . two of the amide - nh doublets disappeared immediately , along with resonances attributable to the n - terminal methylamine protons . however , the other two amide nh resonances , as well as a broad resonance at approximately 8 . 05 ppm , persisted for up to 6 . 5 hours ( fig2 ). these three slowly - exchanging protons are assigned to the amide nhs of trp and d - cha and the side chain amine of lys , the slow exchange behaviour being characteristic of hydrogen - bonding . the amine assignment was established from the tocsy spectrumm where cross peaks were observed between the protonated amine and the ε , δ and γ ch 2 protons . a temperature dependence study ( 20 - 60 ° c .) of the amide - nh chemical shifts ( δδ / t = 2 . 5 ppb / deg , dcha - nh ; 6 ppb / deg , trp - nh ; 6 . 5 ppb , lys - nh ; 8 . 7 ppb , arg - nh ) unambiguously confirmed the involvement of the dcha - nh only in intramolecular hydrogen bonding . a series of 2d 1 h - nmr spectra were measured for 7 at 24 ° c . in d 6 - dmso to determine the three - dimensional structure . tocsy and dfq - cosy experiments were used to identify residue types , while sequential assignments were made from analysis of noesy data . from a series of 100 structures generated from noesy data , fifty of the lowest energy structures were subjected to restrained molecular dynamics ( 200k - 500k ) and energy minimised . a set of 20 calculated structures with a root mean square deviation ( rmsd )& lt ; 0 . 5 å ( backbone atoms ) are superimposed in fig3 and clearly depict a turn conformation . in combination , the nmr constraint data , 3 nh - cαh values , deuterium exchange and temperature dependence data establish an unusual turn structure for hexapeptide 7 which is constrained by up to three hydrogen bonds , as shown in fig4 . the evidence is very strong for one intramolecular hydrogen bond from dcha - nh . . . oc - lys ( 2 . 72 å , n — h . . . o angle 157 °, c ═ o . . . h angle 84 °), forming a 7 - membered ring that defines an inverse γ - turn . the dchanh — o - trpnh angle is 56 . 4 °. the deuterium exchange data and nmr constraint data together point to a second intramolecular hydrogen bond trp - nh . . . oc - lys ( 3 . 31 å , n — h . . . o angle 159 °, co . . . h angle 137 . 3 °) forming a 10 - membered ring characteristic of a β - turn . the φ and ψ angles ( φ 2 =− 58 . 4 °, ψ 2 = 62 . 0 °; φ = 96 . 6 °, ψ 3 = 16 . 6 °) most closely match a type ii β - turn ( bandekar , 1993 ; hutchinson and thornton , 1994 ) which is distorted by the presence of the γ - turn wholly within the β - turn . to our knowledge this is the first example of an intramolecular hydrogen bond between residues within a β - turn , although there are many examples of hydrogen bonds between a residue within the “ 10 membered ring ” of a β - turn and a residue outside of it ( bandekar , 1993 ). a third hydrogen bond ( 2 . 76 å , n — h . . . o angle 160 . 3 °), between the side - chain amine of lys and the c - terminal carboxylate , is suggested by the nmr constraint data , by slow nh / nd exchange and by detection of a weak noe between lys - nh . . . trp - αch 2 . this may further constrain the molecule into the observed turn conformation . such ion - pairing is common in dipolar aprotic solvents such as dimethylsulphoxide and may also be relevant in a hydrophobic protein environment . nmr solution structures have also been determined for several of the cyclic antagonists described in the following examples , and show that in each case the type ii β - turn is preserved and stabilized by the cyclic structure . the constraining β and γ turns proposed in the linear peptide 7 have parallels in cyclic peptides . we have previously detected overlapping β and γ turns in a cyclic octapeptide from ascidiacyclamide ( abbenante et al , 1996 ). combinations of a β - and γ - turn have also been found in the backbones of cyclic penta - and hexapeptides , particularly those containing alternating d - and l - amino acids ( marraud and aubry 1996 ; fairlie et al , 1995 ; kessler et al , 1995 ; stradley et al , 1990 ). for example a type ii β - turn and an inverse γ - turn have been identified in cyclic antagonists c -( d - glu - ala - d - allo - ile - leu - d - trp ] ( ihara et al , 1991 ; coles et al , 1993 ; ihara et al , 1992 ; bean et al , 1994 ) and c -( d - asp - pro - d - val - leu - d - trp ) ( bean et al , 1994 ) for endothelin receptors , and in members of the rhodopsin family of g protein - coupled receptors with seven transmembrane domains ( x . - m . cheng et al , 1994 ). in the latter case , as in 7 , an inverse γ - turn forms between residues ( asp - co . . . val - nh , lys - co . . . dcha - nh ) that flank the proline . we also examined the receptor - binding and antagonist activity of the hexapeptide 7 for comparison with our compounds . the previous - report by konteatis et al ( 1994 ) concerned the ability of 7 to compete with c5a binding to receptors on isolated pmn membranes ( ic 50 70 nm ), which is not necessarily physiologically relevant . we examined competition between 7 and c5a using intact pmn cells , and found that , under these conditions , 7 binds with much lower receptor affinity of ic 50 1 . 8 μm . we confirmed that 7 is a full antagonist with no agonist properties . these results are summarized in fig5 a and table 4 . the relative affinity ( ratio ) of 7 for the c5ar in intact pmns in our assays was similar to that previously reported for isolated pmn membranes . we have also found that 7 shows antagonist activity against both c5a ( fig5 b ) and a c - terminal agonist decapeptide analogue 4 ( ysfkpmplar ) ( finch et al , 1997 ) of the c - terminus c5a 65 - 74 , suggesting that it acts on site 2 of the receptor . compounds 7 and 4 have similar μm affinity for the receptor c5ar on intact polymorphonuclear leukocytes , as shown in table 4 . a new discovery from the data in table 4 is the linear correlation between the log of binding affinities and the log of antagonist potencies for these site 2 antagonists ( compounds 7 - 12 , table 4 ). the importance of this linear relationship is that since receptor affinity and antagonist activity are directly proportional , the experimentally simpler approach of measuring receptor binding may be used to estimate the antagonist activity for such small compounds , provided that there is no evidence of agonist activity . it has previously been proposed that the c - terminus of c5a and of agonist peptides is essential for activity , due to its interaction with a positively - charged arg206 of the receptor ( demartino et al , 1995 ). we confirm here that the c - terminal carboxylate is indeed important for activity ( 8 vs . 7 ), but wondered whether the origin of this effect might be due to hydrogen bonding between the carboxylate anion and the positively charged amine side chain of lys . conversion to the amide ( 8 ) certainly reduces both receptor - affinity and antagonist activity approximately 5 - fold . changing chirality of the arg - cα ( 9 vs . 7 ) causes a similar reduction in activity , and replacing dcha with the less bulky leu residue ( 10 ) is also detrimental to receptor binding . however , potency is recovered for cyclic compounds 11 and 12 , in which an amide bond is tolerated at the c - terminus , consistent with the structural interpretation above that the advantage of the carboxylate in 7 may be associated with intramolecular hydrogen bonding . the replacement of this hydrogen bond it 7 with a covalent amide bond in 11 and 12 more effectively stabilizes the turn conformation . fig5 c compares c5ar binding and antagonist potency in vitro on human pmns for compounds 15 and 17 with those for compound 7 . both 15 and 17 are potent inhibitors at nm concentrations of the action of c5a and the binding of 125i - c 5a to its receptor ( e . g . 4 , kb = 1 . 4 nm ). their cyclic nature and the acetylation at the n - terminal phenylalanine both protect against the proteolytic degradation typically encountered by peptides , making such cyclic compounds more suitable than acyclic peptides as drug candidates . the results are shown in table 5 . some examples of these cyclic antagonists and their apparent receptor - binding affinities and antagonist potencies are given in tables 4 , 5 and 6 as well as in fig5 and 6 . in the tables the single letter code for amino acids is used . ( 2 ) that one of the two possible cyclic diastereomers is consistently favoured for binding to the c5a receptor , and it is surprisingly the opposite stereochemistry ( l - arginine ) to that favoured in the linear compounds ( d - arginine ) ( 3 ) that the cycles have an optimum ring size for receptor - binding , ( 4 ) that there is a pseudo - linear relationship between log ( antagonist potency ) and log ( receptor affinity ). tables 5 and 6 list the c5a receptor affinities of some examples of cyclic antagonists of c5a , and their ability to bind to , and inhibit , binding of c5a to human pmns is illustrated in fig6 . surprisingly these data show that the l - arginine is preferred over the d - arginine , in contrast to the linear compound 7 in which the d - arginine confers higher affinity for the receptor than does l - arginine . the data also show that the size of the macrocycle is optimal when n = 2 or 3 , the smaller cycle where n = 1 and the larger cycle when n = 4 being clearly less active . this requirement for a tightly constrained cycle is probably due to the need to correctly position the attached side chain residues of , for example , trp , dcha , arg and phe for interaction with the receptor . fig7 compares the computer - modelled structure of the cyclic antagonist 12 with the nmr solution structure for the acyclic antagonist 7 . these backbone structures are strikingly similar , and strongly suggest that the receptor - binding conformations of these molecules involve the same turn structure . compound 12 , a more potent antagonist than 11 , also has a shorter linker , which tightens the turn and slightly alters the conformational space accessible to the key side chains of phe , dcha , trp and arg . the conformational limitations placed on the hexapeptide derivative 12 by the cycle are responsible for a ≧ 10 4 increase in receptor - binding affinity over the conformationally flexible decapeptide c - terminus of c5a ( 1 , table 2 ). there is a correlation between binding affinities and antagonist potency for the site 2 antagonists ( compounds 7 - 12 , table 2 ). it thus appears that antagonist potency is dependent upon changes that occur at site 2 alone . without wishing to be bound by any proposed mechanism , we believe that this may be because the mechanism of antagonism is related to conformational change to a turn conformation induced by 7 at site 2 of the receptor . currently there is no information about different types of c5ars . we have previously shown marked differences in the responsiveness of different cells containing functional c5ars to agonists ( sanderson et al , 1994 , 1995 ; finch et al , 1997 ) and we can now provide more information by examining potency and efficacy of selective agonists and antagonists relative to human recombinant c5a . for agonists , the tissue or cell selectivity may reveal functionally different receptors . binding assays using human pmns , u937 cells , or circulating monocytes are used to determine affinities for c5ars . selectivity for different c5ars is ascertained by differential antagonism . this combined approach allows pharmacological characterisation of new agonists or antagonists , and may lead to a potential functional classification of c5arson different cells . compounds were evaluated in an acute model of c5a - induced neutropenia . transient neutropenia maximises 5 min after i . v . c5a and is profound , with & gt ; 90 % of circulating neutrophils disappearing from circulation at effective doses of c5a , as shown in fig8 . the neutropenia is due to transient adherence of circulating neutrophils to the vascular endothelium . preliminary data show that neutropenia caused by i . v . c5a is blocked by a c5a antagonist . for example , f -[ opdchawr ], ( 1 mg / kg ), given prior to 2 μg c5a i . v ., inhibits c5a - induced neutropenia in vivo ( fig8 ) lps causes rapid neutropenia in rats . if this effect of lps is blocked by c5a antagonists , then c5a may be of major importance in the acute effects of lps , and the results shown in fig9 were in agreement with this hypothesis . c5a antagonists were injected ( bolus i . v .) 10 min prior to challenge with lps . rats were anaesthetised , and blood samples ( 0 . 3 ml ) were taken for measurements of pmns . pmns are isolated and quantified . preliminary results show that f -[ opdchawr ], ( 1 mg / kg ), given prior to i . v . lps , inhibits neutropenia . the results also indicate that the c5a antagonist inhibits the increase in haematocrit caused by lps , showing that vascular leakage of serum caused by lps is also inhibited . these results demonstrate that c5a receptor antagonists , such as those described in this invention , may have therapeutic utility in septicaemic individuals . the ability to inhibit the adherence of pmns to vascular endothelium , and to inhibit the vascular leakage to lps as shown by the reduction of haematocrit values , indicates powerful anti - inflammatory effects of these compounds against proinflammatory stimuli activating the complement system , such as endotoxin or lps . preliminary experiments in rats have revealed that the cyclic antagonists summarized in table 5 are active at less than 20 mg / kg as anti - inflammatory agents in suppressing the onset of either carrageenan - induced paw oedema or adjuvant - induced polyarthritis . the maximally effective dosages for even moderately - effective antagonists are 10 mg / kg or less , given i . p . or p . o . many anti - inflammatory drugs currently used in humans were initially evaluated in such assays , and also showed activity in these rat models of inflammation . these preliminary indications of efficacy in vivo indicate that c5a antagonists have therapeutic potential in human inflammatory conditions . using the rat carageenan paw oedema assay , we found that a compound , acf -[ o — p - dcha - w - r ], which is 100 times less active than 17 in vitro as a c5a antagonist in pmns , has some in vivo activity in rats given 1 mg / kg of the compound i . p , 30 min prior to the carageenan injection . paw swelling was measured for up to 4 . 5 hr . the results , shown in fig1 , suggest that even this weak c5a antagonist significantly inhibits development of the oedema after 180 and 270 min . this anti - inflammatory activity suggests that c5a receptor antagonists , such as those described in this invention , may have therapeutic activity in diseases involving vascular leakage following inflammatory stimuli . in recent years there have been many attempts to mimic β - and γ - turn peptides that represent bioactive protein surfaces , resulting in notable mimetics for rgd ( arginine - glycine - aspartate ) peptides , somatostatin and opioid peptides , to name a few derived through structure - activity relationships ( see for example marraud and aubry , 1996 ; fairlie et al , 1995 ). most of these examples preserve a turn structure through cyclisation of the peptide . on the other hand , there are comparatively few short acyclic peptides that have been found to have substantial turn structure in solution ( dyson et al , 1988 ; rizo and gierasch , 1992 ; pràcheur et al , 1994 ). it is usually argued that short acyclic peptides adopt a myriad of solution structures that may include small populations of turn structures that are responsible for bioactivity . this invention describes a series of conformationally - constrained turn - containing molecules that are preorganized for binding to the same g protein - coupled receptor ( s ) of human cells that are targeted by human c5a . the invention is applicable to other c protein - coupled receptors . the principal feature of the compounds of the invention is the preorganized arrangement , which brings at least three hydrophobic groups and a charged group into neighbouring space , creating a hydrophobic surface ‘ patch ’. these results enable the design and development of even more potent conformationally - constrained , small molecule antagonists of c5a . in the light of the aforementioned prior art , it was surprising to find that a c - terminal carboxylate was not necessary in our compounds in order to obtain good receptor - binding or antagonist activity . the cyclic antagonists have an amide bond at the ‘ c - terminal ’ arginine position . the replacement of the carboxylate in 7 with a covalent amide bond effectively stabilises the required turn conformation . cyclic and non - peptidic antagonists have several important advantages over peptides as drugs . the cycles described in this invention are stable to proteolytic degradation for at least several hours at 37 ° c . in human blood or plasma , or in human or rat gastric juices or in the presence of digestive enzymes such as pepsin , trypsin and chymotrypsin . in contrast , short peptides composed of l - amino acids are rapidly degraded to their component amino acids within a few minutes under these conditions . a second advantage lies in the constrained single conformations adopted by the cyclic and non - peptidic molecules , whereas acyclic or linear peptides are flexible enough to adopt several structures in solution other than the required receptor - binding structure . thirdly , cyclic and non - peptidic compounds such as those described in this invention are usually more lipid - soluble and more pharmacologically bioavailable as drugs than peptides , which can rarely be administered orally . fourthly , the plasma half - lives of cyclic and non - peptidic molecules are usually longer than those of peptides . it will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding , various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification . references cited herein are listed on the following pages , and are incorporated herein by this reference . abbenante , g ., fairlie , d . p ., gahan , l . r ., hanson , g . r ., pierens , g . k . and van den brenk , a . l . j . am . chem . soc ., 1996 118 10384 - 10388 bean , j . w ., peishoff , c . e . and kopple , k . d . int . j . protein res ., 1994 44 223 cheng , x . m ., doherty , a . m ., nikam , s . s . curr . med . chem . 1994 1 271 - 312 coles , m ., sowemimo , v ., scanlon , d ., munro , s . l . a ., craik , d . j . j . med . chem ., 1993 36 2658 demartino , j . a ., konteatis , z . d ., siciliano , s . j ., van riper , g ., underwood , d . j ., fischer , p . a ., springer , m . s . j . biol . chem ., 1995 270 15966 - 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the present invention relates to novel cyclic or constrained acyclic compounds which modulate the activity of g protein - coupled receptors and are useful in the treatment of conditions mediated by g protein - coupled receptors , for example , inflammatory conditions .