Guinea Pig Platelet Aggregation Research Articles

Effect of coenzyme Q10 andArdisia japonicaBlume on plasma and liver lipids, platelet aggregation, and erythrocyte Na efflux channels in simvastatin-treated guinea pigs

Forty guinea pigs were divided into four groups and fed 0.04% cholesterol based control diet, plus 0.05% simvastatin, and statin plus 0.1% CoQ10 or 10% Ardisia Japonica Blume (AJB) leave powder for 4 weeks. Plasma total cholesterol levels decreased significantly in all groups fed the statin-containing diet compared with that in guinea pigs fed the control diet (P < 0.01). Plasma and liver triglycerides decreased significantly in the statin plus CoQ10 group compared with those in the control (both P < 0.05). Maximum platelet aggregation was significantly higher in the statin plus CoQ10 group than that in the other groups (P < 0.05). Na-K ATPase activity increased in the statin group and decreased in the statin plus CoQ10 group (P < 0.01). Na-K co-transport and Na passive transport decreased significantly in the control group compared with those in the other groups (both P < 0.05). Intracellular Na was highest in the statin group and lowest in the statin plus CoQ10 group and was correlated with Na-K ATPase activity. Thiobarbituric acid reactive substance production in platelet-rich plasma and liver tended to decrease in the statin plus CoQ10 group compared with those in the other groups. Plasma glutamic-pyruvic transaminase and glutamic-oxaloacetic transaminase increased significantly in the statin group compared with those in the control (P < 0.05). These result suggest that antioxidant rich AJB did not have positive effects on cardiovascular disease parameters. The statin plus CoQ10 seemed to decrease cholesterol more efficiently than that of statin alone.

The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs

Thrombin is a powerful agonist for platelets, the action of which is mediated by the thrombin receptor protease-activated receptor-1 (PAR-1). Recently, we discovered that E5555 (1-(3- tert-butyl-4-methoxy-5-morpholinophenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-2 H-isoindol-2-yl) ethanone hydrobromide) is a potent thrombin receptor antagonist. We evaluated the anti-platelet and anti-thrombotic effects of E5555. E5555 inhibited the binding of a high-affinity thrombin receptor-activating peptide ([ 3H]haTRAP) to PAR-1 with a half maximal inhibitory concentration (IC 50) value of 0.019 μM. E5555 showed potent inhibitory effects on human platelet aggregation induced by thrombin and TRAP with IC 50 values of 0.064 and 0.031 μM, respectively, but had no effect on platelet aggregation induced by either ADP or collagen. Similarly, E5555 showed potent and selective inhibitory effects on guinea pig platelet aggregation induced by thrombin and TRAP with IC 50 values of 0.13 and 0.097 μM, respectively. The antithrombotic activity of E5555 in vivo was evaluated in a photochemically-induced thrombosis (PIT) model using guinea pigs. Oral administration of E5555 at 30 and 100 mg/kg prolonged the time to occlusion by 1.8-fold and 2.4-fold, respectively, compared with controls. Furthermore, E5555 did not prolong bleeding time in guinea pigs at the highest tested dosage of 1000 mg/kg. The drug interactions between E5555 and tissue plasminogen activator (tPA) were evaluated. Intravenous administration of 1 mg/kg tPA significantly prolonged bleeding time, and its effects were not altered by the oral co-administration of 300 mg/kg E5555. These results suggest that E5555 could be a therapeutic option for atherothrombotic disease.

ChemInform Abstract: Thromboxane A2 Receptor Antagonists. Synthesis and Activities of Phenylsulfonamido Derivatives.

Abstract A number of phenylsulfonamido derivatives have been synthesized and tested for their ability to inhibit: a) thromboxane A 2 /prostaglandin H 2 ( TXA 2 PGH 2 ) mimetic (U46619)- induced guinea pig platelet aggregation; b) aortic ring contraction; and c) binding of a radioiodinated TXA 2 PGH 2 mimetic (I-BOP) to platelets. In platelet, K d values ranged from 9 nM to > 50 μM. p K b values in aortic rings ranged from 7.63 to 3.66 and in platelets from 7.7 to K d and p K b values found in the 3 systems. Antagonist activity at the TXA 2 PGH 2 receptor was sensitive to both the substitution pattern of the 2 aromatic rings and the presence of heteroatoms. For 2 of the derivatives ( 4 and 11 ) molecular mechanics calculations were performed which indicated subtle structural differences that may account for the > 300-fold difference in potency observed for these analogs at the platelet TXA 2 PGH 2 receptor.

Selective conjugated fatty acids inhibit guinea pig platelet aggregation

Conjugated linoleic acids have been shown to reduce eicosanoid release from select tissues and/or cells. To elucidate effects of conjugated linoleic acid isomers on cyclooxygenase-1 (COX-1) activity and their application as platelet aggregation inhibitors, conjugated linoleic acid isomers and conjugated nonadecadienoic acid were incubated with ovine COX-1 and Raw264.7 macrophage to examine their effects on COX-1 activity. The effects were further examined in collagen and ADP-induced guinea pig whole blood platelet aggregation. Fatty acids tested were shown to inhibit COX-1 enzymatic activity. However, only 10t, 12c-conjugated linoleic acid, 9t, 11t-conjugated linoleic acid and conjugated nonadecadienoic acid inhibited collagen and ADP-induced platelet aggregation with IC 50 125.9 μM (74.2 μM to 213.4 μM, 95% confidence interval), 99.3 μM (52.8 μM to 187.2 μM, 95% confidence interval) and 124.3 μM (85.1 μM to 181.5 μM, 95% confidence interval) respectively in collagen-induced aggregation. TxB 2 release was also appreciably inhibited by 10t, 12c-conjugated linoleic acid, 9t, 11t-conjugated linoleic acid and conjugated nonadecadienoic acid. Based on these data, we conclude 10t, 12c-conjugated linoleic acid, 9t, 11t-conjugated linoleic acid and conjugated nonadecadienoic acid are platelet aggregation inhibitors while 9c, 11t-conjugated linoleic acid is a moderate inhibitor and linoleic acid, and 9c, 11c-conjugated linoleic acid have no effect on whole blood platelet aggregation.

A Novel Dual Antagonist of Thromboxane A2 and Leukotriene D4 Receptors: Synthesis and Structure-Activity Relationships of Chloroquinolylvinyl Derivatives

To discover an orally active thromboxane A(2) (TXA(2)) and leukotriene D(4) (LTD(4)) dual antagonist, we designed and synthesized chloroquinolylvinyl derivatives based on the structures of the TXA(2) antagonist daltroban and the LTD(4) antagonist montelukast. Among these derivatives, 4-{[(2-(4-chlorophenylsulfonylamino)-1-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)thio]methyl}benzoic acid (18d) showed potent inhibitory activity against U46619-induced aggregation of guinea pig platelets and LTD(4)-induced contraction in the guinea pig ileum, with IC(50) values of 340 nm and 0.40 nm, respectively. Oral administration of 18 d also inhibited both the LTD(4)-induced acceleration of plasma leakage to skin in guinea pig and the U46619-induced increase in airway resistance in guinea pig with ED(50) values of 0.47 mg/kg and 3.3 mg/kg, respectively.

Restoration of middle cerebral artery thrombosis by novel glycoprotein IIb/IIIa antagonist FK419 in guinea pig

We compared the antithrombotic efficacy of FK419 [( S)-2-acetylamino-3-[( R)-[1-[3-(piperidin-4-yl)propionyl]piperidin-3-ylcarbonyl]amino] propionic acid trihydrate], a novel nonpeptide glycoprotein IIb/IIIa antagonist, with recombinant tissue plasminogen activator (rt-PA) and other antithrombotic agents (aspirin, ozagrel, argatroban and heparin). FK419 not only inhibited ADP- and collagen-induced guinea pig platelet aggregation, but also induced disaggregation for ADP-induced aggregated platelets in vitro. In the photochemically induced middle cerebral artery thrombosis model in guinea pigs, FK419 dose-dependently shortened the time to first reperfusion and the total middle cerebral artery occlusion time and reduced ischemic brain damage and ameliorated neurological deficits measured 24 h after middle cerebral artery occlusion. Rt-PA similarly improved the middle cerebral artery patency, brain damage and neurological deficits. Neither aspirin, ozagrel, argatroban nor heparin restored the middle cerebral artery blood flow and improved the brain damage or neurological deficits. These results demonstrated that novel glycoprotein IIb/IIIa antagonist FK419 could disperse thrombus and ameliorated ischemic brain damage, suggesting that FK419 would be an attractive intervention for stroke patients.

Characterization of the anti‐platelet actions of FK419, a novel non‐peptide antagonist of platelet GPIIb/IIIa

AbstractThe anti‐platelet properties of FK419 ((S)‐2‐acetylamino‐3‐[(R)‐[1‐[3‐(piperidin‐4‐yl)propionyl]piperidin‐3‐ylcarbonyl] amino]propionic acid), a novel non‐peptide GPIIb/IIIa antagonist, were compared in a variety of experimental settings, both in vitro and in vivo, with other GPIIb/IIIa antagonists including xemilofiban, lamifiban, tirofiban, and FK633. Receptor binding studies suggested that FK419 had potent GPIIb/IIIa antagonistic activity that is comparable with those of reference antagonists. FK419 effectively inhibited human platelet aggregation, regardless of agonist stimuli (IC50 = 35–170 nM). FK419 demonstrated in vitro species‐dependent anti‐platelet activity, with higher potency in human than in dog, guinea pig, or rat tissue, and dose‐dependently inhibited ex vivo platelet aggregation in dogs and guinea pigs. In contrast to other antagonists, FK419 minimally affected template bleeding time at doses that completely inhibited platelet aggregation in canines. These results demonstrate that FK419 is a novel, potent, and selective GPIIb/IIIa antagonist that safely inhibits platelet aggregation in vivo, suggesting that it may be a promising anti‐platelet agent for thrombotic diseases. Drug Dev. Res. 61:233–241, 2004. © 2004 Wiley‐Liss, Inc.

Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig

The antiplatelet and antithrombotic effects of FR171113, 3-(4-chlorophenyl)-2-(2,4-dichlorobenzoylimino)-5-(methoxycarbonyl methylene)-1,3-thiazolidin-4-one, a non-peptide protease-activated receptor 1 (PAR1) antagonist, were evaluated in guinea pigs. FR171113 inhibited Ser–Phe–Leu–Leu–Arg–Asn–NH2 (a synthetic PAR1 agonist peptide)-induced and thrombin-induced aggregation of guinea pig platelets in a concentration-dependent manner in vitro (IC50=1.5 and 0.35 μM, respectively). Subcutaneous administration of FR171113 (0.1–3.2 mg/kg) produced a dose-dependent inhibition of platelet aggregation ex vivo. The ED50 value of FR171113 for platelet aggregation was 0.49 mg/kg s.c. However, FR171113 did not have an inhibitory effect on ADP- or collagen-induced platelet aggregation in vitro and ex vivo. One hour after FR171113 treatment at 1.0 mg/kg s.c., significant inhibition of arterial thrombosis without a prolongation of thrombin time or coagulation time was seen in the FeCl3-induced carotid artery thrombosis model in guinea pigs. Furthermore, FR171113 did not prolong bleeding time even at 32 mg/kg s.c., which is a much higher dose than that required in the thrombosis model. These observations indicate that FR171113 has desirable antiplatelet effects both in vitro and in vivo and that its in vivo antithrombotic activity is efficacious without causing a prolongation of bleeding time.

Orally active GPIIb/IIIa antagonists: synthesis and biological activities of masked amidines as prodrugs of 2-[(3S)-4.

To improve the in vivo potency of the potent GPIIb/IIIa antagonist 2-[(3S)-4-[(2S)-2-(4-amidinobenzoylamino)-3-(4-methoxyphenyl)propanoyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyljacetic acid (4), the amidino group was converted to an oxadiazole ring, thiadiazole ring or substituted amidoxime group. These groups were expected to be metabolized to an amidino group in vivo. The compounds synthesized were evaluated for their potency to inhibit the ex vivo adenosine 5'-diphosphate (ADP)-induced aggregation of guinea pig platelets. Among the compounds examined, the methoxycarbonyloxyamidine 8a exhibited the most potent ex vivo inhibitory activity with a fast onset and prolonged duration of action after oral administration.

Antiplatelet and Antithrombotic Effect of D-003

D-003 is a mixture of higher primary aliphatic saturated acids purified from sugar cane wax whose main component is octacosanoic acid followed by triacontanoic, dotriacontanoic, and tetratriacontanoic acids. The aim of this study was to evaluate the effects of D-003 on: ex vivo platelet aggregation, arterial thrombosis and bleeding time in rats. In addition, time course of antiplatelet effects of D-003 was also investigated on ex vivo platelet aggregation in guinea-pigs. D-003 (25–200 mg kg−1) orally administered at single or repeated doses (3 days) inhibited platelet aggregation induced by collagen (2.2 μ g ml−1) and ADP (2μ mol l−1) in rats, and collagen (0.25 μ g ml−1) induced aggregation in guinea-pigs in a dose-dependent manner. Single doses of D-003 (5–500 mg kg−1) administered orally 2 h before induction of arterial thrombosis significantly inhibited the reduction of rectal temperature. D-003 administered at a single dose (50–200 mg kg−1) 2 h before the experiment significantly increased the bleeding time in a dose-dependent manner. The time-course effects of D-003 on platelet aggregation, arterial thrombus formation, and bleeding time showed no effect 0.5 h after dosing, and maximal effects exhibited 1–2 h after treatment, whereas no significant effects were found 4 h after treatment.

Antiplatelet and Antithrombotic Effects of Orbofiban, a New Orally Active GPIIb/IIIa Antagonist, in Guinea Pigs

Antiplatelet and antithrombotic effects of orbofiban, a new orally active glycoprotein IIb/IIIa antagonist, were evaluated in guinea pigs. SC-57101A (0.03–1 μM), the hydrochloride salt of the active form of orbofiban, inhibited in vitro ADP- and collagen-induced platelet aggregation in a concentration-dependent manner. Oral administration of orbofiban (3–30 mg/kg) resulted in dose-dependent inhibition of ADP- and collagen-induced platelet aggregation. The inhibition peaked at 1–2 hours postdose and then declined slowly. The agent also showed similar inhibition of platelet aggregation in guinea pigs with dietary-induced hypercholesterolemia. In contrast, the antiaggregatory effects of acetylsalicylic acid differed more widely between normal and hyperlipidemic animals compared to those of orbofiban. Plasma concentration of the active form, measured by a column-switching HPLC method, correlated well with the inhibition of platelet aggregation. Orbofiban (3–100 mg/kg, p.o.) caused dose-dependent inhibition of thrombus formation in an arteriovenous-shunt-thrombosis model. Orbofiban at high doses (⩾30 mg/kg) and acetylsalicylic acid (100 mg/kg) both prolonged cutaneous bleeding time measured by the template method. These results demonstrate that orbofiban is an orally active and potent inhibitor of platelet aggregation with an efficacy that correlates well with the plasma concentration of its active form.

Antiplatelet effect of Z-335, a new orally active and long-lasting thromboxane receptor antagonist

We investigated the pharmacological characteristics of Z-335 ((±)-sodium[2-[4-(chlorophenylsulfonylaminomethyl)indan-5-yl]acetate monohydrate), a new indan derivative. Z-335 inhibited the specific binding of [ 3 H ]SQ-29548 to human platelets and guinea pig platelet membranes. The IC 50 values of Z-335 for human platelets and guinea pig platelet membranes were 29.9±3.1 nM with a slope of 1.09±0.05 and 32.5±1.7 nM with a slope of 1.07±0.02, respectively. Z-335 inhibited thromboxane A 2 receptor-mediated human and guinea pig platelet aggregation in vitro and oral administration of this drug to guinea pigs inhibited U-46619- and collagen-induced platelet aggregation for 24 h. Z-335 dose-dependently prevented the occurrence of U-46619-induced pulmonary thromboembolism in mice and the protective effect of this drug (0.3 and 3 mg/kg, p.o.) lasted for 24 h. These results strongly suggest that Z-335 is a potent, orally active and long-lasting thromboxane A 2 receptor antagonist, which may be useful as an antiplatelet drug.

Novel non-peptide fibrinogen receptor antagonists. 1. Synthesis and glycoprotein IIb-IIIa antagonistic activities of 1,3,4-trisubstituted 2-oxopiperazine derivatives incorporating side-chain functions of the RGDF peptide.

Based on the lead tetrapeptide RGDF, two possible non-peptide glycoprotein (GP) IIb-IIIa antagonists possessing an (S)-2-oxopiperazine-3-acetic acid moiety as a scaffold incorporating the indispensable Asp fragment were prepared, and (S)-4-[[trans-[4-(guanidinomethyl)-cyclohexyl]carbonyl]glycyl]-2- oxopiperazine-1,3-diacetic acid, 1a, was identified as a potential lead. A series of 3-substituted 2-oxopiperazine-1-acetic acids bearing the Arg-Gly equivalent at the 4-position were prepared and evaluated for their ability to prevent platelet aggregation and for their binding affinity for the GP IIb-IIIa receptor purified from human HEL cells. (S)-4-[(4-Amidinobenzoyl)glycyl]-3-[(methoxycarbonyl)methyl]- 2-oxopiperazine-1-acetic acid, 9 (TAK-029), inhibited in vitro human platelet aggregation with an IC50 value of 0.03 microM and GP IIb-IIIa-fibrinogen binding with an IC50 value of 0.49 nM. The [4-(2-aminoethyl)benzoyl]glycyl derivative 26 showed activity comparable to that of 9 (IC50 = 0.093 microM, guinea pig platelet aggregation assay). Compound 9 dose-dependently inhibited ex vivo platelet aggregation in guinea pigs (0.03 and 0.1 mg/kg, i.v.), and long-lasting inhibition of platelet aggregation was observed upon oral administration of 9 (3 mg/kg) to guinea pigs. On the other hand, the activity of 26 disappeared within 1 h after a dose of 1 mg/kg (i.v.). Compound 9 may therefore be useful in the clinical treatment of arterial thrombotic diseases.

O-253 - Inhibitory effects of FR171113, a novel, thrombin receptor antagonist, on platelet aggregation and thrombosis model in guinea-pigs

O-253 - Inhibitory effects of FR171113, a novel, thrombin receptor antagonist, on platelet aggregation and thrombosis model in guinea-pigs

Effects of taurine on calcium in platelets and their aggregation.

Taurine concentrations are 400-fold greater in platelets than in plasma1, 5. The role of taurine in platelets has not been elucidated. For cardiologists, platelet taurine content is likely to have diagnostic value, since a decrease in taurine concentration in these cells indirectly reflects changes in taurine level in body tissues in general and in heart in particular11. Paasonen et al. 12 have reported that the taurine level in patients with hypertension does not differ from control values but increases in patients with myocardial infarction. In platelets, taurine transport decreases both in hypertension and in cardiovascular failure9. Marked losses of taurine from animals or humans affects the functional state of not only such organs as heart13 and retina8 but also of platelets. Taurine is known to model Ca2+ responses to PAF3. Taurine can inhibit PAF-induced aggregation of guinea pig platelets and aggregation of human platelets induced by ADP, serotonin and epinephrine2. Hayes et al. 9 reported the interrelation of taurine status and platelet aggregation in cat. They discovered that marked loss of taurine from platelets make them more sensitive to aggregation. These authors assume that this effect can be mediated via changes in GSH and altered thromboxane liberation. We suppose that this effect of taurine is not its only platelet action. Taurine may possess a homeostatic action that is revealed in certain pathological conditions. For this reason we have studied taurine effects in cells obtained from donors with different rhythm disturbances.

Synthesis and thromboxane A2 antagonistic activity of [[1-aryl(or benzyl)-1-(benzenesulfonamido)methyl]phenyl]alkanoic acid derivatives.

In order to find new antiasthmatic and antithrombotic agents, various [[1-aryl(or benzyl)-1-(benzenesulfonamido)methyl]phenyl]alkanoic acid derivatives were synthesized. Evaluation of these compounds for thromboxane A2 (TXA2) antagonistic activities indicated that 4-[4-[(4-chlorobenzenesulfonamido)phenylmethyl]phenyl]butyric acid (6h) ,4-[4-[1-(4-chlorobenzenesulfonamido)-2-phenylethyl]phenyl]butyric acid (6y) and many other compounds have potent inhibitory effects on U-46619-induced guinea-pig platelet aggregation. No significant difference in the inhibitory effect between (+)-6h and its antipode could be detected, although (+)-6h and its antipode could be detected, although (+)-6y was about 10 times more potent than (-)6y. The pKb values of 6h and 6y were estimated to be 8.9 and 10, respectively on U-46619-induced contraction of guinea-pig trachea as a pharmacological measure of TXA2 antagonistic activity. These compounds also showed potent inhibitory effects on U-46619-induced bronchoconstriction in guinea-pig after oral administration in vivo. They were also evaluated for other related pharmacological effects involving the arachidonic acid cascade. It was found that these compounds possess TXA2 synthase inhibitory activity together with TXA2 antagonistic activity, and 6h also possesses weak leukotriene D4 (LTD4) antagonistic activity. Structure-activity relationships for TXA2 antagonistic activity of these derivatives are discussed.

Synthesis of [[(benzenesulfonamido)alkyl]phenyl]alkanoic acid derivatives containing pyridyl or imidazolyl groups and their thromboxane A2 receptor antagonistic and thromboxane A2 synthase inhibitory activities.

As part of our search for a dual inhibitor possessing both thromboxane A2 (TXA2) receptor antagonistic and TXA2 synthase inhibitory activities, some [[(benzenesulfonamido)alkyl]phenyl]alkanoic acid derivatives possessing a pyridyl or imidazolyl group were synthesized. Their TXA2 receptor antagonistic and TXA2 synthase inhibitory activities were evaluated in terms of the inhibitory effects on U-46619-induced guinea-pig platelet aggregation and on thromboxane B2 (TXB2) production in human platelets, respectively. It was found that 3-[4-[2-(1-imidazolyl)-1-(4-chlorobenzenesulfonamido)ethyl]phenyl] propionic acid (22a), containing an imidazolyl group, is a well-balanced dual inhibitor having both TXA2 receptor antagonistic activity (IC50 = 0.31 microM) and TXA2 synthase inhibitory activity (IC50 = 0.39 microM).

The extracellular neutral cysteine proteinase of Entamoeba histolytica degrades anaphylatoxins C3a and C5a.

We have shown previously that the extracellular cysteine proteinase of Entamoeba histolytica trophozoites activates the alternative pathway of complement by specifically cleaving C3. This unique mechanism of complement activation leads to passive lysis of nonpathogenic, but not of pathogenic strains. In an attempt to investigate the relationship between the cleavage of complement components C3 and C5 and the pathogenesis of amebiasis, we investigated the production of the anaphylatoxins C3a and C5a, which have diverse effects on the host immune response. The concentration of proteinase required to cleave purified C5 was at least 5 to 10 times that needed for C3 cleavage, but these levels are easily obtainable as demonstrated by cleavage of 125I-labeled C5 during incubation with purified trophozoites. When the C3a-like cleavage fragments were purified by gel filtration, they were found to be extensively degraded during a 1-h incubation of C3 with the proteinase. Subsequent evaluations of the C3a- and C5a-like cleavage products generated earlier in the reaction using immunoblots and cellulose acetate electrophoresis revealed rapid degradation, even during incubation periods as short as 5 min. Because C-terminal fragments as small as 20 amino acid residues can mimic the biologic functions of C3a or C5a, we tested cleavage products for activity. In sensitive bioassays, including guinea pig platelet aggregation for C3a activity and chemotaxis for C5a activity, we demonstrated that proteolysis renders these molecules inactive. These studies suggest that the extracellular cysteine proteinase of E. histolytica, which is capable of activating the complement system, may also provide a mechanism to circumvent normal host immunity by inactivating the proinflammatory factors C3a and C5a.

P3-125 - Effects of PGEI suppository on platelet aggregation and thrombus formation in guinea-pigs

P3-125 - Effects of PGEI suppository on platelet aggregation and thrombus formation in guinea-pigs

Decapeptide agonists of human C5a: the relationship between conformation and spasmogenic and platelet aggregatory activities.

A series of decapeptide analogues corresponding to the C-terminal region of human C5a anaphylatoxin (C5a65-74) was synthesized with residue substitutions to restrict conformational flexibility in the C-terminus. These conformationally constrained peptides behaved as agonists of C5a in spasmogenic assays (smooth muscle contraction in human fetal artery, guinea pig ileum, and guinea pig lung parenchyma) as well as guinea pig platelet aggregation. There were significant correlations in the potencies of these peptides between the various assays. A structure-function analysis led to the identification of a preferred backbone conformation that correlated with the expression of these biological responses. These backbone structural motifs were consistent with a helix-like conformation for residues 65-69, an elongated structure for residues 70-71, and a beta-turn of either type II or type V for residues (71)72-74. The most potent of these agonists expressed almost 5% of the potency of natural C5a.