Hypothermic response produced by Manassantin A, a novel neuroleptic agent

Life Sciences,Vol. 42, pp. 2717-2720 Printed in the U.S.A.

PergantonPress

cblleq9ofFhaImacy, nepartmentof~~chemistry, J.HillisHiLlerHedlthcenter,~~ityof~~~, Gainesville,F'L32610 (Receivedin final form May 2, 1988)

EfaMssantinA(MIS-A),anovelmoligmid,m&ral~ehmn topceseeexEulmleptic~es,causeehypathermicrespolmsain mlearrlfmalemiceofCD1strainkhen&mM&er& bytheintrace?xbxwentritiar (icv), (0.1, 1.0, 3.2, 10 /q&use), intraperitcneal (ip), (0.1, 0.32, 1.0, 3.2 nq/kg) aM oral (0.5, 1.6, 5.0, 16nq/kq)xuutes. lbehypothermiawasfamdtobedceeandtime dependent,themaximm!decrease oftqYz?zltlDxbeilqckeervedby lbicvrarte (Pc0.001)after2 haxs. rkwever,i.pandoralachninistsati~ofl~andmiddleo~doses~natveryeffective lxthigherdceescausedsignificant (p
*m: Malearrl femdLemiceof CDlstrain, 20-30g (30-45 days old) cMzunedfmm~e6River,EPL,~used.~animals~housedina billed (23 f 2'C) IDam maintained at a I.2kurlightanddark 23b&UdpelletdietandWitiwater~iMa!d cycleandmprwidedwitha 1ibitlZU. MNS-Ais relativelyineolubleinwater,andlPlifcnu ew==ia===F=0.4% cH-cBllulct3eboraladmw&rati== pared in 0.9% saline ocrrtaining ad&nbbatialt3w8r.xmadebyusing ca.rriedartusitqaf~canrula,arrdip finediqowbleneedlee. zhevoluneofchug~

HaleyandMabzmick(3),exceptwith

a slightxxlificati~thatasleeved25

0024-3205188$3.00 + .OO Copyright (c) 1988 Pergamon Press Plc

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Hypothermic Response Produced by MNS-A

gaqemedlewasusedan3thewd.lewverpemtratadnnrethan2.5nm.

Rectal

8lectmnicallywi~asmdllanimal~e imertedafterlubricaticcl,toackpthof ~(~~DFish=), mmaimci for 30 sec. 2.5 cm. ~lzxmsmre moox&d ~Yaftar~probe memtalixqmammw~ admmstmtialandl, bsfo.mthednq 3,5ana8Iwursafterthsdrugwas ~bytheipandoIalmutes.In theicv-injectedanimals,therectdL~+lmas~~~dfo~daeirq arrl0.5, 1, 1.5, 2, 3, 5 and 8 hatrs post k&y. lkn animals were used for ea&&selevel. ---

Derta:Allthe~~~,~.edinthethreefiguresaremean+ thestatist.ical S.E.M. A IZWItailed stUezks't3t88twaswedtodstemim A p value of CO.05 w aa'midered 8ignifkanoeinvarious~~~groups. asstati.stical1 3ignificant.

zheeffectsofip~ordl~ti~ofvariausdoeesofENS-Aare meoartrolnliot3,lxeatedwith5mWkgofthe fammrixdinFig~rxsland2. rxmnalsaline aaRainingO.4%~lulose,bytheiporozalmutesdidnot showsignifkant&anrjesinthsbodYtqxmtum. W-Agiwmbythsipmxte causezllcxw&~~ of the boay temperature (Fig. 1) but tha &amje was not significar? at the lcnmr doses: 0.1 a& 0.32 x@cg. Ihe middle o&er dose of 1 q/kg ot the drug pKCdm3d 8ignificarIt(p
0

-12

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2

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T*IE hourd Fb.

1 Effect ol b MN&A

on tha body tm~~hw.

Fig. 1

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HypothermicReeponee Produced by MNS-A

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PCO.06

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Fig. 2 Mminkkmtia~ of &W-A at 0.1, 1.0, 3.2 and 10 w w the icw Iuuta caut3edstatisticdlly~fioant~ (PcO.001)inulebodyt&qemtmB of oulsoiaasmioe (Fig. 3). memen?&EtlmswlKeckwialSwiUl.inthefin3t hourof&f3iIy. lrcklarandmicklledo6watmmd ===yb==lUtu= betwmthe5thandmkU?skuteve!natm.istilm,tbex.wUcti~in~ Ihe 10 /KJ ~tlXXXWZISStillt3i&.fiCaIlt&E?Il~WiUltheCXXltMS. ofocmmiausmioe. In &s8cau6edalO-ll*CmIwticminthebody~ trJlogrrrupsOfmioe,the10~doee~~f~~~gitFenbytheiP rrrute. Likmise,nxrmndLsalinewith0.4%a4-oelluloeewas ineffectivein ocmoiammioe,~gi~bytheicvrouta. laJeringthebody~tW?in

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Hypothermic Response Produced by

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MNS-A

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TM2 Chaur)

ft~uw~n*** to O.l-lop2 of tdns-A at SO-100 mlnut8r WI.,. ~IOnlflcantly dlttwent from control at p
Fig. 3 the neuroleptic profileof MN%A resemblesthat ~~pri==Y====, ofmsexpine, al~theremybedifferen=es intheirmdesofaction. The ~~~fileofreserpinehasbeenstudiedby~~investigators anditsabilitytocausedepletianofcatecholamine~~hasservedas aninvestigativeandtxeabmnttoolin vcolcgy. Itisnotclearat thiepoint whetherthe MM-A-iMuoed hypatherrma is due to depletionof catecholaminesoreemtmininthecentral nemxseyetemor~ oth=systaas are irwolved,suchasthepmstaglarxLinsorcpioidpeptidee.ThesestMiesare beingamtimed.

Amtherintemet~pc6eibilityisthatMNS-A-i.ndw&hyp&hemic ~maybeusefulasan~~modelforevdluat~anti~~ dmg!sasreeerpineiebeingused cmmmtly. Manyantidepreesant -antagmizeulehypolbnu 'cxEspaseproducedbyreserpine. lscmver,theuseof W-A for this pwpcee can have advantagescverthatofreserpinebecause,the hypathermicnqcmewith~-Area-its llbuinminabart1_2harrswhereas, with msexpine, this my take 24-48hoursti givenby the ip or oral rmtee. W-A, beiq a ~tmgenas cmpamzlofancnrelstnxtum, maymrkbya differentm&arnsmardmayexterdtheutilityofthieteet.

The authorswishto mpreee aFpreciaticnt0NIMiforthegrantsupport, FXX Mi36039.

I.&t.24 4947-4950(1983). 1. K.V. RAiDand F.M. AT.,,, %bat&mm 2. K.V. RAO, V.N. RIRI,P. DIWANand F.M. AL-, Rmmaml. F&s. amnun. u 629-632(1987). 3. T.J. H?UX and W.C. McXX%MICK,Brit.J. l%axmacol. 'Ihemp.12 12-15 (1957). 4. A. PLEISCHER,B.B. BRXXE and P.A. sH3wE,Scieme m 374-375(1955).