57

E.iP 5273.3

Pulmonary actions of LY255283, a leukotriene

4 receptor antagonist

Steven A. Silbaugh, Peter W. Stengel, Sandra L. Cockerham, Garlos R. Roman, David L, Saussy, Stephen M. Spaethe, Theodore Goodson, Jr., David K. Herron and Jerome H. Fleisch hdtrror~ury

t?eviwrch Dqurmm,

.L.il!\? &wmf~

_bdwumric.s,

Eli Idi&

utrcl Cot~putr~,

itdiaijupdi.~,

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Received 23 March 1992. revised MS received IS July lYY2. accepted1 t August 19~2

The actiuns of LY255283, a lcukotricnc (LT) B, reccptcrr antug(~nist,were examined on guinea pig lung. LTB, and LY2552X3 displaced [‘HJLTB, from its binding site on lung mcmbrancs with pK, values of 9.9 and 7.0, rcspcctivcly. In the functional corrclatc of lhc binding studies, LY2552X3 compctitivcly rcduccd conlractilc responsesof lung parcnchyma to LTB, (pA, = 7.2). LTB., produced airway obstruction which was rcduccd by LY255283 administered i-v. (EDs,, = 2.X ,ng/kg) or arri!:; (ED,,, = 11.0 .._. . . _ m&k&. Coniraciiic rChtjoiw.2 (13kisi~uikiC, ‘LTZ, and t!:c :hrcmh::r,nnr mimetic, t_t4h6!9i cvcrc not reduced by LY255283. The ~(~rn~~und also did nut inhibit cyclt~(~xyg~nasc or S-lip~~~gc~~as~cnzymcs. WC conclude that LY2SS28.1 sclcctivcly ~nt~g~)n~~~d pharmacologic rcsponscs to LTB, on lung tissue and appearsto he a useful tool to invcstigatc the role of LTB, in pulmonary discasc. L~uk(~tri~n~ B,; Rcccpttrr billdin~: ~r~ilchyrnu~ c~)ntru~tion~Airway ~)bstructi(~tl:~~~uk~~tri~n~ B, rcccptor ~nt~g~~nists~ (Guinea-pig)

Leukotricnc B, (LTB,), a dihydroxy metabolite of arachidonic acid, is a potent stimulant of granulocytc aggregation and chcmotaxis and may also have immunorcgulatory properties (Lewis et ai., i98i; Good= win, 1986; Dahindcn ct al., 1984; Drazcn and Austcn, 19871. This lipid is thought to play a role in scvcral inflammatory disorders (Ford-Hutchinson, 1990~. Conccntrations of LTB, arc increased within the bronchoalveolar lovage fluid of asthmatics (Wardlaw et al., 1989k the skin lesions of psor~aticsand individu~~lswith atopic dermatitis (Rosenbach ct al., 19851, and the mucosa of patients with inflammatory bowel disease (Sharon and Stenson, 19841. If the role of LTB, in thcsc and other diseases is to be clearly detcrmin~d, LTB, receptor antagonjsts with well-dcfincd properties are needed. However, only a few such agents have been described to date (Gapinski et al., 1988; Herron et al., 1988; Lawson et al., 1989; Tsai et al., 1983; Kunno et al., 1990). With the exception of SC-41930 (Li et al., 1990, Villani-Price et al., 1992), charac!criza-

tion of these LTB, receptor ant~~gon~sts has been limited. Preliminary reports indicated that LY255283 (fig. I) is an cffectivc LTB, rcccptor antagonist both in vitro and in viva {Jackson et al., t988a.b). This compound is a po:cnt :..h:R:*,-,~ ,*,,,11111,,,of LTB, hinrlinu n‘8... . ..._ tn _. !~~!m;!n ~CIItrophils and also blocks LTB,-induced aggregation of guinea pig l~cutr~?phils(Jackson et al., 1988a). In rabbits, LY255283 reduced the transient ncutropenia following i.v. LTB, administration (Jackson et al., 19KSb). In rats, it inhibited antigen-induced pulmonary eos~nophil influx (Richards ct al., 199Of. LY25528.7 is of particular interest because of rcccnt reports of its ability to reduce the pathophysiologic scquclae of shock induced by cndotoxin (Li ct al.. I9911 or splanchnic riftcry occlusion (~ara~~~~~ c: a!.. !99!! In the rat. LY255283 also has been shown to reduce the pul-

boxnnc (TX) A, mimetic IBOP ([I!3 In.2,%X),3a(lE. 3S * ),4n )]-7-[3-(S-hydroxy-4-(4’-iodophent~xy:y)- I -hutcnacid) yl)-7-0xilbicyclt~ [ 7.3. I]hep!nn-7-yl]S-heptanc~ic from their binding sitcs on guinea pig lung membranes. /-‘H]LTD, and [ ““I]IROP binding wcrc pcrformcd as dcscrihed by O’Sullivitn al. ( 19) 11, respcctiscly.

Guinea

pigs were

and Mong ( 14%‘)) and Saus~y et

kttlcd

by CO,

suffocation

and

subscyuent decapitation. Lungs were excised and perfused through the pulmonary artcty with Krchs-bicarbonittc solution of the following composi!ion

in mM:

KCI 4.0; KH ,PO, 1.2; MgSO, * 7H,O 1.2; NaCl 11X.2; NaHCO, 24.X; dextrose 10.0 and CaCI, * 2H,O 2.5. S!rips

of pitrcrtchyma wcrc rcmtwcd

cdgc of R...A.. La*I

I

&%I+-f;liliillillRCd.

nx:!c

:!u!brcd

H;tr!!c

5’

guinc:t

pigs wc’rc obtained fmtn C’hnrlcs Kivtx i3recding Lahonttories (I%lrt;tgc, MI) ;IIKI housctl in stainless steel ventil;t!cd KtCk cages.

l‘hcy

wcrc provided foiPd (Purinn

the lung

and the

from

ends sccurcd

the attcr by cotton

thread. The tissues wcrc then placed in 10 ml organ was I?::!hS Under it pa&c fi.?rcc

Pulmonary actions of LY255283, a leukotriene B4 receptor antagonist.

The actions of LY255283, a leukotriene (LT) B4 receptor antagonist, were examined on guinea pig lung. LTB4 and LY255283 displaced [3H]LTB4 from its bi...
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