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Dopaminergic and antioxidant activity of a benz[g]indolamine derivative
Relating
Me4enoonlin
to Invited Lecture 3 & 8-Pharmacology
pepttdes are a group of sbucture9y refeted pepbdes Met
derive from e common precumor, vn (PofvtC). They have e veriety of functbns both in the perfphery and in the Central nervous system. Ftve dtfferent suwypsr of MSH mceptcm heve been cloned end eequenced, but Iktfe b known ebout their functional roles. MSH~sh~acors~~wm*)s~tlrrlforMndkrgto melenocorth receptors. However, y-MSH peptldea netunlfy show a very low effinfty for the MCI mceptor compmed to a-f&H, whereas at the MC3 mceptcr, affinltbs of oMSH and T-M3H ere dmller to eech other. AstheN-tem*rdMdofthe~e~~shownto~ddispensll~ for binding end bk&gwel ectfwty at those receptors. Therefore, the sefectivity of the pepgdes is likely to be debrmined withln the C-terminaI portion. Also, the structureI dhrimilarity between u-MSH and T-MSH in in se&&v@. theCitermlndrwglonsuggestsin vdvemant In our study, nplrcrmsnt of p&ne ln posftfcn 12 of a-M3H with either phenylefenfne 01 efenfne led to kss e&e prptides; however, pPhe’ analogues of a-MSH were not effeUed by m+cement of position 12 wfth phenybtenke, serfne or budne. At the seme bme bfndhg of T-MSH totheMClncrp(oraKlldkin~~~e~e~uewas inbuduced in me po&tlon conwpondkrg to met in a-H. Our~~thaPlo”Is~v,trsq~tforhighaffnity binding to and bblogk~l ecth4ty et the MCI mceptor. The coneeponding resldue in +SH, phenyiebnlne, however, does not appear to confer any selectfvky for the MC3 mceptor, &though T-MSHb thought by some to be the neturel Hgendfor the mceptor (Roseki-Rehfuss ef a/., 1993, Proc. Ned. Aced. Sd. USA BQ,sss6seeo).
Determfnetbn of beta-In In dffferent regions of the brain kterndorphlnfevefetinderfheef&Zbleome rmmefed~fn kdMnQrphln fevele and approprfate mdrUBe.Cb=4feefn ~fneomebmInregbnemfghtbeh~wftbd~ In~eyetem.TheeKkbde&*changesIn ~teveftnthebratnendeerumofrrtaaRertheueeof flwo%embIe detemtfned et d&nfte ume hneival8. study wae carded out onedult~~~olbo(h~.Oncgroupotanlmrls(Brsts) wee edmfnietemd I.p. ftwoxam fneeduSonInadoeeof2m@kgofbody wefgM durfng 24 houn. The eecond group of anlmafs (6 rate) wae tnatcd~~Mme~~daedfl~mhwfocgdays.Thtcootrd groupdenbneb@r&a)ws&@nMMmdtheappr@eMamountof bsta-cndorphln In the braln phyelobgkefeoMbrl.~of Ueeueeendeereofrateweredetermlnedbylmmunon6Kc method (1). TheNhMdWeLJg@etthet: . the-of-, Inadeffydoeeof2m@gofrata’ bocfymeee,prcn&edaefgnffkentbcreaeelneerumbete-endorphln fetmf durfng 24 houre (75.84 f 2.78 p@nL), and 9 daye after the beebmntbl ccqer@nCconbdgroup(34.4Sil.ll5pg/mL). 9-d bstccndorphkrfnthebralnffeeueeofratewere efgn&entfy lower (SSQ.72* 15.71 p&) durfng 24 hours and 9 days gs27.57*32 pg/g) after fhe admmteambn ofadaffydoeeof2mglkg of fluvoxamlne in comperfaon to conbof group (873% 18.32 pslg) The exf&me&l reeufb mveded chengee In the level of beta+ndorphlnInlheeemendbmtntbeueeof~enlmals undertbe~dnwoxemble.~dmngeemeybethereeunofan increnedeecmtkmof w rebeehg hormone (CRF) lncludlng thea&atfonofthe~ gland axfe ate eerotonln. 1) Durovlc D., Mejki&Siih N. The EffeU of emkriptyline on the level of &sndorphin in we rem end ne~ous tissues of rats. Abstracts book FIP 1995.Stoc#olm (Abstrac4no 221).
& Drug Receptors (Pl.O79-PI
.lOO)
s119
This study was designed to evaluate if and to what extsnt motphine3-gbcuronide (M3G) antagonise morphine antino+eptive effects and also if M3G is involved in the development of acute tolerance. An addkional objective was to study the impact of M3G on the respiratory function after morphine (M) administration. The rat.9received M HCI as an infusion for 3 hours, 10 rng/hkg (A) or 20 mg/hkg (B). Both groups were pretreated with saline infusion (I), MBG-infusion (4,3 mgWkg) (II) or MBG-infusion (17,4 m@?Vkg) (Ill). As the morphine infusion started the M3G i sion was stepwfae decreased to correct for the formed M3 .The expertmental eeffect design included measurement of the antinoci (electricaf stimulation vocafisatbn) and of respi ry parameters 4 &CO,, pG,. pfi). Plasma samples were anafysed or M and M3G. Acute tolerance developed to the antlnocicapthm effect in all groups. For both M doses the subgroup with the highest M3G infusion rate (Ill) tended to have more pronounced tolerance development. M3G infusion (Ill) influenced the an inociceptlve effecf after M, so that no incrwaee in AUEC was obee 4 d with the two-fold increase in dose of M. When saline (I) or M3G inftfefon (II) was administered the AUEC increased by a fador two. The result suggen a competftiie interadion between M andlits metabofiie. However, the extent of this interaction is not large. M depresses respiration with increased pCO,and decreased p0, in blood as a result. The AUEC for p0, was significantly lowered by M3G-pretreatment in group A (pcO.05). No acute tolerance developed to the respiratory effects. M3G kept Pa, at more physiological levels, which indicate that M3G may pby a role in reduction of the development of respiratory disorders sometimes seen after M administration.
vlty. The maximum reducbon of activity (40%) as observed at a dose of 4@mollkg. b) In reserpine pretreated rat 1 Induces a dosedependent (40. 50. lti(kmobka) hvoeractivr behawor. c) (n apomorphirie pretr&te&rats, 1 (&lpmolrkg) rev&& the hyperactivity induced by apomorphine. The above results may Indicate that 1 acts as a central dopaminergic paffial agonist. The antioxidant potential of 1 was studied in thk following models: a)h vitro lipid peroxidation. It was found that 1 strongly lnhibiis the peroxidation of liver microsome preparations. It shows acbvrty comparable to that of vitamine E, since its activity is reduced only at concentrations
Me4enoonlin
to Invited Lecture 3 & 8-Pharmacology
pepttdes are a group of sbucture9y refeted pepbdes Met
derive from e common precumor, vn (PofvtC). They have e veriety of functbns both in the perfphery and in the Central nervous system. Ftve dtfferent suwypsr of MSH mceptcm heve been cloned end eequenced, but Iktfe b known ebout their functional roles. MSH~sh~acors~~wm*)s~tlrrlforMndkrgto melenocorth receptors. However, y-MSH peptldea netunlfy show a very low effinfty for the MCI mceptor compmed to a-f&H, whereas at the MC3 mceptcr, affinltbs of oMSH and T-M3H ere dmller to eech other. AstheN-tem*rdMdofthe~e~~shownto~ddispensll~ for binding end bk&gwel ectfwty at those receptors. Therefore, the sefectivity of the pepgdes is likely to be debrmined withln the C-terminaI portion. Also, the structureI dhrimilarity between u-MSH and T-MSH in in se&&v@. theCitermlndrwglonsuggestsin vdvemant In our study, nplrcrmsnt of p&ne ln posftfcn 12 of a-M3H with either phenylefenfne 01 efenfne led to kss e&e prptides; however, pPhe’ analogues of a-MSH were not effeUed by m+cement of position 12 wfth phenybtenke, serfne or budne. At the seme bme bfndhg of T-MSH totheMClncrp(oraKlldkin~~~e~e~uewas inbuduced in me po&tlon conwpondkrg to met in a-H. Our~~thaPlo”Is~v,trsq~tforhighaffnity binding to and bblogk~l ecth4ty et the MCI mceptor. The coneeponding resldue in +SH, phenyiebnlne, however, does not appear to confer any selectfvky for the MC3 mceptor, &though T-MSHb thought by some to be the neturel Hgendfor the mceptor (Roseki-Rehfuss ef a/., 1993, Proc. Ned. Aced. Sd. USA BQ,sss6seeo).
Determfnetbn of beta-In In dffferent regions of the brain kterndorphlnfevefetinderfheef&Zbleome rmmefed~fn kdMnQrphln fevele and approprfate mdrUBe.Cb=4feefn ~fneomebmInregbnemfghtbeh~wftbd~ In~eyetem.TheeKkbde&*changesIn ~teveftnthebratnendeerumofrrtaaRertheueeof flwo%embIe detemtfned et d&nfte ume hneival8. study wae carded out onedult~~~olbo(h~.Oncgroupotanlmrls(Brsts) wee edmfnietemd I.p. ftwoxam fneeduSonInadoeeof2m@kgofbody wefgM durfng 24 houn. The eecond group of anlmafs (6 rate) wae tnatcd~~Mme~~daedfl~mhwfocgdays.Thtcootrd groupdenbneb@r&a)ws&@nMMmdtheappr@eMamountof bsta-cndorphln In the braln phyelobgkefeoMbrl.~of Ueeueeendeereofrateweredetermlnedbylmmunon6Kc method (1). TheNhMdWeLJg@etthet: . the-of-, Inadeffydoeeof2m@gofrata’ bocfymeee,prcn&edaefgnffkentbcreaeelneerumbete-endorphln fetmf durfng 24 houre (75.84 f 2.78 p@nL), and 9 daye after the beebmntbl ccqer@nCconbdgroup(34.4Sil.ll5pg/mL). 9-d bstccndorphkrfnthebralnffeeueeofratewere efgn&entfy lower (SSQ.72* 15.71 p&) durfng 24 hours and 9 days gs27.57*32 pg/g) after fhe admmteambn ofadaffydoeeof2mglkg of fluvoxamlne in comperfaon to conbof group (873% 18.32 pslg) The exf&me&l reeufb mveded chengee In the level of beta+ndorphlnInlheeemendbmtntbeueeof~enlmals undertbe~dnwoxemble.~dmngeemeybethereeunofan increnedeecmtkmof w rebeehg hormone (CRF) lncludlng thea&atfonofthe~ gland axfe ate eerotonln. 1) Durovlc D., Mejki&Siih N. The EffeU of emkriptyline on the level of &sndorphin in we rem end ne~ous tissues of rats. Abstracts book FIP 1995.Stoc#olm (Abstrac4no 221).
& Drug Receptors (Pl.O79-PI
.lOO)
s119
This study was designed to evaluate if and to what extsnt motphine3-gbcuronide (M3G) antagonise morphine antino+eptive effects and also if M3G is involved in the development of acute tolerance. An addkional objective was to study the impact of M3G on the respiratory function after morphine (M) administration. The rat.9received M HCI as an infusion for 3 hours, 10 rng/hkg (A) or 20 mg/hkg (B). Both groups were pretreated with saline infusion (I), MBG-infusion (4,3 mgWkg) (II) or MBG-infusion (17,4 m@?Vkg) (Ill). As the morphine infusion started the M3G i sion was stepwfae decreased to correct for the formed M3 .The expertmental eeffect design included measurement of the antinoci (electricaf stimulation vocafisatbn) and of respi ry parameters 4 &CO,, pG,. pfi). Plasma samples were anafysed or M and M3G. Acute tolerance developed to the antlnocicapthm effect in all groups. For both M doses the subgroup with the highest M3G infusion rate (Ill) tended to have more pronounced tolerance development. M3G infusion (Ill) influenced the an inociceptlve effecf after M, so that no incrwaee in AUEC was obee 4 d with the two-fold increase in dose of M. When saline (I) or M3G inftfefon (II) was administered the AUEC increased by a fador two. The result suggen a competftiie interadion between M andlits metabofiie. However, the extent of this interaction is not large. M depresses respiration with increased pCO,and decreased p0, in blood as a result. The AUEC for p0, was significantly lowered by M3G-pretreatment in group A (pcO.05). No acute tolerance developed to the respiratory effects. M3G kept Pa, at more physiological levels, which indicate that M3G may pby a role in reduction of the development of respiratory disorders sometimes seen after M administration.
vlty. The maximum reducbon of activity (40%) as observed at a dose of 4@mollkg. b) In reserpine pretreated rat 1 Induces a dosedependent (40. 50. lti(kmobka) hvoeractivr behawor. c) (n apomorphirie pretr&te&rats, 1 (&lpmolrkg) rev&& the hyperactivity induced by apomorphine. The above results may Indicate that 1 acts as a central dopaminergic paffial agonist. The antioxidant potential of 1 was studied in thk following models: a)h vitro lipid peroxidation. It was found that 1 strongly lnhibiis the peroxidation of liver microsome preparations. It shows acbvrty comparable to that of vitamine E, since its activity is reduced only at concentrations