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A E Takemori

Publications and source records attributed to A E Takemori.

At least 73 records · Page 4Linked to original sources
PubMed1991

Role of spacer and address components in peptidomimetic delta opioid receptor antagonists related to naltrindole.

A series of heterocyclic analogues 2-5 related to naltrindole (1) (NTI) and 6-arylnaltrexone derivatives 6-8 were synthesized in order to determine the role of the spacer and the address moieties in conferring delta opioid receptor antagonist activity. The benzofuran (NTB), quinoxaline, and quinoline analogues (2, 3, and 4, respectively) were delta-selective opioid antagonists in vitro and bound selectively to delta receptors. The tetrahydroindole derivative 5, while delta-selective, was considerably less potent than its indole analogue 13. The data for 2-4 indicate that heterocycles other than pyrrole can serve as a spacer for the delta address moiety. Moreover, the lower delta antagonist potency of 5 illustrates the importance of the aromatic address component. Molecular dynamics simulations of enkephalin using a zipper binding model are consistent with a delta address subsite that may accommodate the benzene moiety of NTI or the Phe4 phenyl group of leucine enkephalin. The considerably lower delta opioid receptor antagonist potencies of the 6-aryl derivatives 6-8 are consistent with the conformational mobility of the aryl group and its location in the molecule.

Animals↗
PubMed1991

Differential antagonism of opioid delta antinociception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5'-isothiocyanate: evidence for delta receptor subtypes.

The present study has investigated the direct opioid delta receptor-mediated antinociception produced by i.c.v. administration of the highly selective delta agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2]deltorphin II, as well as that of the less delta-selective [D-Ser2,Leu5,Thr6]enkephalin (DSLET), by using two novel nonequilibrium opioid antagonists, [D-Ala2,Leu5,Cys6] enkephalin (DALCE) and naltrindole 5'-isothiocyanate (5'-NTII). At times ranging from 8 to 48 hr after a single i.c.v. pretreatment of mice with 5'-NTII, the antinociceptive effects of [D-Ala2] deltorphin II were significantly antagonized. In contrast, 5'-NTII pretreatment at times between 10 min and 24 hr failed to antagonize the antinociceptive effects of DPDPE. Previous studies have shown that pretreatment with i.c.v. DALCE produces a dose- and time-related antagonism of DPDPE, but not morphine, antinociception. However, pretreatment with i.c.v. DALCE failed to antagonize the antinociceptive effects of [D-Ala2]deltorphin II. Similarly, i.c.v. administration of DSLET produced time- and dose-related antinociception which was partially antagonized by either beta-funaltrexamine (beta-FNA) or by ICI 174,864 (N,N-dialyl-Tyr-Aib-Aib-Phe-Leu-OH), suggesting mixed activity at mu and delta receptors. ICI 174,864 produced essentially complete antagonism of DSLET antinociception in beta-FNA-pretreated mice. Pretreatment with 5'-NTII (at -8 to -48 hr), blocked the antinociception produced by DSLET in control or in beta-FNA-pretreated mice. In contrast, pretreatment with DALCE failed to antagonize the antinociception produced by i.c.v. DSLET in either control or in beta-FNA-pretreated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1991

Isobolographic analysis of analgesic interactions between intrathecally and intracerebroventricularly administered fentanyl, morphine and D-Ala2-D-Leu5-enkephalin in morphine-tolerant and nontolerant mice.

Concurrent administration of morphine sulfate i.c.v. and i.t. produces a multiplicative interaction for analgesia in the tail flick response in mice. This interaction decreases to an additive interaction in mice which are tolerant to s.c. morphine. To test the responses of opioids selective for mu or delta receptors, the present study examined the interactions between fentanyl citrate (mu agonist) and D-Ala2-D-Leu5 enkephalin (DADLE, a relatively selective delta agonist) administered i.c.v. and i.t. using the tail flick test in control and morphine pellet-implanted mice. A method was developed for assigning statistical significance to the resulting ED50 values when analyzed isobolographically. When fentanyl or DADLE was administered i.c.v. plus i.t., an additive interaction between sites occurred in control animals, which changed to an antagonistic interaction for fentanyl and a multiplicative interaction for DADLE after morphine pellet treatment. When morphine was given i.c.v. along with i.t. fentanyl or DADLE in control animals, multiplicative interactions occurred when equipotent doses were given. Thus, opioids which were more receptor-selective than morphine did not produce multiplicative interactions, but were multiplicative when given with morphine. These results suggest that activation of combinations of receptors (by morphine) was required for the multiplicative interaction. The supraspinal site involved mu receptors (which are not self-sufficient and require an additional component) and the spinal site involved mu or delta receptors. The use of isobolographic analysis required that the drugs, when administered concurrently at two sites, be given in a constant dose ratio.

Animals↗
PubMed1991

Antagonism of morphine antinociception by intrathecally administered corticotropin-releasing factor in mice.

Intrathecally (i.t.) administered corticotropin-releasing factor (CRF) has been shown to produce antinociception in the mouse abdominal stretching (writhing) assay. It also has been demonstrated that spinal kappa opioid receptors as well as CRF receptors are involved in the antinociception induced by CRF. In the present study, the role of CRF i.t. in modulating nociception was assessed further using the mouse tail-flick test. In addition, the modulatory effect of i.t. administered CRF on the antinociceptive activity of morphine was studied. Despite its potent and long-lasting antinociceptive effect in the writhing assay, CRF injected i.t. produced no consistent antinociception in the tail-flick test at doses up to 20 times the antinociceptive ED50 of CRF in the writhing test. In contrast, i.t. injection of CRF significantly attenuated the antinociceptive action of s.c. administered morphine. CRF at doses of 0.1 and 0.2 nmol/mouse i.t. increased the antinociceptive ED50 of s.c. morphine by 2- and 4-fold, respectively. The antagonistic action of CRF peaked between 15 min and 1 hr after i.t. injection and was still observable 4 hr after injection, demonstrating a time course similar to that of the antinociceptive effect of CRF in the writhing test. Intrathecal injection of alpha-helical CRF(9-41), a competitive CRF receptor antagonist, was able to inhibit, in a dose-dependent manner, the antagonistic activity of CRF. The antagonistic action of CRF also was attenuated dose-dependently by i.t. injection of nor-binaltorphimine (nor-BNI), a highly selective kappa opioid receptor antagonist. However, intrathecal injection of (+)-1-nor-BNI, an inactive enantiomer of nor-BNI, did not affect the antagonistic action of CRF. These data suggest that spinal kappa opioid receptors as well as CRF receptors are involved in the antagonistic effect of CRF against morphine antinociception.

Analgesia↗
PubMed1991

Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice: evidence for delta opioid receptor subtypes.

In this study naltrindole (NTI) and its benzofuran derivative (NTB) were studied for their antagonist activity against various delta opioid receptor agonists in the tail-flick antinociceptive assay in mice. The antinociceptive ED50 of i.c.v. administered DSLET [(D-Ser2, Leu5, Thr6)enkephalin] was shifted about 4-fold by either s.c. NTB or i.c.v. NTI injection. On the other hand, the antinociceptive ED50 of i.c.v. administered DPDPE [(D-Pen2,D-Pen5)enkephalin] was shifted 1.4- and 1.8-fold with s.c. NTB and i.c.v. NTI administration, respectively, which were significantly lower than the shifts observed with DSLET. NTB did not alter the antinociceptive action of i.c.v. administered [(D-Ala2,D-Leu5)enkephalin], morphine sulfate, [(D-Ala2,MePhe4,Gly-ol5)enkephalin] or U-50,488H (trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide). At spinal sites, the antinociceptive ED50 of intrathecal (i.t.) administered DSLET was increased by 12.5-fold by s.c. NTB injection, whereas that of DPDPE was unaffected. NTB injection at this site also did not alter the antinociceptive action of i.t. administered [D-Ala2, D-Leu5]enkephalin, [(D-Ala2,MePhe4,Gly-ol5)enkephalin] or morphine sulfate. Pretreatment of animals with beta-funaltrexamine caused a large increase in the capacity of NTB to antagonize the antinociceptive activity of i.t. administered DSLET with little change in that of i.t. administered DPDPE. When cross-tolerance between DSLET and DPDPE was studied by i.c.v. injection of a single large dose of either DSLET or DPDPE 24 hr before the antinociceptive assay, there was no development of cross-tolerance between the two peptides. Based on these results, it was concluded that the antinociceptive action of DSLET and DPDPE may be mediated by different receptors, possibly delta opioid subtypes.

Analgesia↗
PubMed1990

Long-acting agonist and antagonist activities of naltrexamine bivalent ligands in mice.

A series of naltrexamine bivalent ligands, compounds with two naltrexamine pharmacophores separated by a spacer which contains a variable number of glycyl units flanking a succinyl group, were synthesized and evaluated in vivo in mice. These compounds possessed long-acting agonist and especially antagonist activities. The bivalent ligands, 2 and 3 displayed antinociceptive activity that lasted greater than 4 h. Compound 1, a bivalent ligand and 4, the monomer, antagonized the antinociceptive effect of morphine for a week after a single injection i.c.v. The long duration of action may be due to entrapment of these ligands in the central nervous system. These compounds may give future insights into the design of long-acting agonists and antagonists.

Analgesics↗
PubMed1990

Attenuation of the antinociceptive action of the selective kappa-opioid receptor agonist, U-50,488H by ICS-205-930.

The antinociceptive action of s.c. administered U-50,488H was antagonized by s.c. administered ICS-205-930, a selective 5-HT3 receptor antagonist. To characterize the site of interaction, U-50,488H and ICS-205-930 were administered either intracerebroventricularly (i.c.v.) or intrathecally (i.t.). When U-50,488H was administered i.c.v., its antinociception action was antagonized by ICS-205-930 given either i.c.v. or i.t., increasing the ED50 values of U-50,488H by approximately twofold from 48 to 98 and 90 nmol/mouse, respectively. However, when U-50,488H was administered i.t., its antinociception action was not antagonized by ICS-205-930 given either i.c.v. or i.t. These findings suggest that i.c.v., but not i.t. administered U-50,488H may release serotonin both supraspinally and spinally to interact with 5-HT3 receptors to produce antinociception.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Mediation of nitrous oxide analgesia in mice by spinal and supraspinal kappa-opioid receptors.

Exposure to nitrous oxide produced concentration-dependent analgesia in the mouse abdominal constriction test. Intracerebroventricular or intrathecal pretreatment with naltrexone or nor-binaltorphimine significantly reduced nitrous oxide analgesia. However, similar pretreatment with beta-funaltrexamine had no appreciable effect. These findings suggest that nitrous oxide analgesia involves spinal and supraspinal kappa-opioid receptors.

Analgesics↗
PubMed1990

Design of peptidomimetic delta opioid receptor antagonists using the message-address concept.

Highly selective nonpeptide ligands with potent delta opioid receptor antagonist activity have been developed using the message-address concept. This approach envisaged the delta opioid receptor to contain two major recognition subsites; a message subsite which recognizes the pharmacophore, and an address subsite that is unique for the delta receptor type and confers selectivity. The message and address components of the delta-selective enkephalins were postulated to be Tyr1 and Phe4, respectively, with Gly2-Gly3 functioning as a spacer. The message component of the target compounds in this study was derived from naltrexone and related structures. An indole system was fused to the C ring of naltrexone as a mimic of the address component. The benzene moiety of indole was viewed as the delta address component, mimicking the phenyl group of Phe4, and the pyrrole portion was used as a rigid spacer. Members of the series (1-23) were evaluated for opioid antagonist activity on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Naltrindole (NTI, 1) was the most potent member of the series, with Ke values of approximately 0.1 nM at delta receptors. The antagonism by NTI was approximately 220- and 350-fold greater at delta than at mu and kappa opioid receptors. The binding of NTI and selected members of the series to guinea pig brain membranes was qualitatively consistent with their pharmacologic antagonist activity profiles in the MVD and GPI, but the Ki values were not in the same rank order. The selectivity of NTI arises mainly as a consequence of increased affinity at delta receptors. Thus, the Ke and Ki values of NTI were 1/530 and 1/90 that of the delta antagonist enkephalin analogue, ICI 174864. In contrast to NTI, ICI174864 derives its selectivity through greatly decreased recognition at mu and kappa receptors. The implications of the high affinity and selectivity of NTI as a consequence of its conformational rigidity are discussed. It is suggested that any attempt to model a receptor-bound conformation of an opioid peptide should consider affinity and potency at multiple receptor sites rather than selectivity alone.

Animals↗
PubMed1990

Release by U-50,488H of [3H]serotonin from brain slices and spinal cord synaptosomes of U-50,488H-tolerant and nontolerant mice.

The effect of U-50,488H [trans-(+/-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl) benzeneacetamide] on the release of [3H] serotonin from mouse brain slices and spinal cord synaptosomes was studied using a superfusion system. Release was stimulated with 30 mM K+ while superfusing with Krebs-Ringer buffer, in the presence or absence of U-50,488H (3 nM to 1 microM). In both tissues, U-50,488H resulted in a concentration-related increase in release. The estimated EC50 values were found to be 14 and 42 nM in brain and spinal tissues, respectively. The increase in release was antagonized by 3 x 10(-7) M naloxone. The induction of release was found to be a Ca+(+)-dependent process which was significantly reduced in Ca+(+)-free medium containing ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid. Tolerance to U-50,488H was induced in mice using a slow release method. They were tested with the tail-flick assay to ensure tolerance had developed. The U-50,488H-induced release of [3H] serotonin was observed to decrease from both tissues of the U-50,488H-tolerant animals. These findings suggest that tolerance to the antinociceptive action of U-50,488H is accompanied by a decrease in its ability to stimulate serotonin release from brain and spinal tissues.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Involvement of spinal kappa opioid receptors in the antinociception produced by intrathecally administered corticotropin-releasing factor in mice.

Corticotropin-releasing factor (CRF), a putative stress transmitter, in previous studies failed to show any antinociceptive effect after central intracerebroventricular administration. In this study, a possible role of intrathecally (i.t.) administered CRF in modulating nociception and the involvement of opioid receptors were examined. CRF (i.t.) produced a dose-dependent antinociceptive effect in the mouse abdominal stretching (writhing) assay, with an ED50 of 22.1 (18.9-25.8) pmol/mouse. This antinociceptive effect of CRF peaked from 10 min to 1 hr after i.t. administration, although a significant antinociceptive effect was still observable 4 hr after injection. The dose-response curve of CRF antinociception was shifted to the right by i.t. administered alpha-helical CRF (9-41), a CRF antagonist, and the ED50 was raised by 3.7-fold. Naloxone, an opioid antagonist, also dose-dependently shifted the antinociceptive dose-response curve of CRF to the right. Naloxone at 1 and 10 mg/kg s.c. increased the ED50 value of CRF by 2- and 4-fold, respectively. In contrast, s.c. injection of 10 mg/kg of (+)-naltrexone, an inactive enantiomer of naltrexone, did not affect significantly the antinociception of i.t. administered CRF. Intrathecal injection of nor-binaltorphimine, a highly selective kappa opioid antagonist, increased the antinociceptive ED50 of CRF by 5.6-fold. However, the antinociceptive activity of CRF (i.t.) was not significantly affected by either beta-funaltrexamine, an irreversible mu selective opioid antagonist, or naltrindole, a highly selective delta opioid antagonist. Furthermore, the antinociceptive ED50 of CRF was not altered by (+)-1-nor-binaltorphimine, an inactive enantiomer of nor-binaltorphimine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Naloxone produces protracted tolerance in mice treated with a single dose of morphine.

Previously we have shown that naloxone (NLX)-induced withdrawal in acutely dependent mice [a single dose of 100 mg/kg of morphine sulfate (MS) s.c.] leads to an increase in the degree and duration of the dependent state. In this study we investigated the modulation of opioid tolerance by NLX in acutely tolerant mice (a single dose of 100 mg/kg of MS s.c.). When acutely tolerant mice were injected 3 hr later with 32 mg/kg of NLX, tolerance to the antinociceptive effect of MS could be observed for at least 12 days after MS injection. The same dose of NLX given 3 days after MS injection also led to the prolongation of MS tolerance whereas 4 mg/kg of NLX had no effect. By using the latter protocol, if the ineffective 4-mg/kg dose of NLX was preceded 2 hr before with 10 mg/kg of MS, tolerance to MS could be detected for at least 6 days. When this protracted tolerance (100 mg/kg of MS followed 3 hr later by 32 mg/kg of NLX) was studied at spinal and supraspinal sites, tolerance to MS at supraspinal sites was greater and more prolonged than at spinal sites. [D-Pen2,D-Pen5]enkephalin did not show cross-tolerance at either site. U50,488H [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)-cyclohexyl]benzeneacetamide) showed a slowly developing cross-tolerance only at the supraspinal sites. In acutely tolerant animals, the tolerance that developed at supraspinal and spinal sites was of equal magnitude and contributed additively to the total tolerance observed in the animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1990

Maintenance of morphine dependence by naloxone in acutely dependent mice.

To investigate the development of dependence to a single dose of morphine sulfate (MS) and its modulation by naloxone hydrochloride (NLX), mice were pretreated with a single dose of MS, 100 mg/kg s.c. and, at various times after this pretreatment, a priming dose of 10 mg/kg of MS s.c. was administered. Two hours later various doses of NLX were injected s.c. to precipitate jumping behavior, a sign of withdrawal and ED50 values of NLX were determined. Twenty-four and 72 hr after the MS pretreatment, NLX ED50 values were 18 and 21 mg/kg, respectively, which were significantly lower than those of the control groups which did not receive the 100 mg/kg of MS pretreatment. If the withdrawn mice were reprimed with a 10 mg/kg s.c. dose of MS 24 and 72 hr after the first priming dose, they displayed even more sensitivity to NLX with the NLX ED50 values lowered to 3 and 4 mg/kg, respectively. In addition, mice pretreated with 100 mg/kg of MS and treated with 32 mg/kg of NLX either 1 or 3 days later required smaller amounts of NLX to precipitate withdrawal after the priming dose of MS. NLX ED50 values in the former group were 5 and 4 mg/kg 24 and 72 hr after MS injection, respectively. In the latter group NLX ED50 values were 2, 19 and 25 mg/kg after 4, 6 and 9 days after MS injection, respectively. All these values were significantly lower than those of control groups which did not receive NLX at 3 or 72 hr after 100 mg/kg of MS. These results suggest that administration of the opioid antagonist naloxone in morphine-pretreated mice can lead to the maintenance of the dependent state.

Animals↗
PubMed1989

The use of mu opioid receptors in the mouse vas deferens for the study of opiate tolerance.

We have previously shown that mu opioid receptors in the guinea pig ileum preparations are poor models for those in the central nervous system to study the phenomenon of opiate tolerance. Since we have shown subsequently that the mu opioid receptors in the mouse vas deferens preparation differ from those in the guinea pig ileum, we investigated the possibility that the mu receptors in the mouse vas deferens might be better models for the study of opiate tolerance. The degree of tolerance produced by incubation of mouse vas deferens preparations with morphine in vitro was relatively low. However, when mice were either implanted with morphine pellets (75 mg free base) or injected s.c. with 100, 50 or 25 mg/kg of morphine sulfate, a large magnitude of tolerance in their vasa deferentia was consistently observed. When pA2 analyses were performed in the tolerant vasa deferentia (25 mg/kg) using naloxone, the pA2 value was 7.55 +/- 0.18 compared to the control value of 8.45 +/- 0.24. Since the tissue became significantly more refractory to the effects of the opiate antagonist with the development of tolerance, which is the opposite of what happens with central mu receptors, we conclude that the mu opioid receptors in the mouse vas deferens are not adequate models for those in the central nervous system to study the phenomenon of tolerance.

Animals↗
PubMed1989

Selective kappa antagonist properties of nor-binaltorphimine in the rat MES seizure model.

The opioid antagonist properties of nor-binaltorphimine (nor-BNI; 17,17'-Bis(cyclopropylmethyl)-6,6',7,7'-tetradehydro-4,5:4', 5'-diepoxy-6,6'-(imino) [7,7'-bimorphinan]-3,3',14,14'-tetrol) were evaluated in vivo in the rat maximal electroshock (MES) seizure model. Following s.c. or i.c.v. pretreatment, nor-BNI selectively antagonized the anticonvulsant effects of the kappa opioid U50, 488, significantly increasing its ED50 by 2.3 and 4.5 fold, respectively. In contrast, pretreatment with nor-BNI (s.c. or i.c.v.) failed to antagonize the anticonvulsant effects of the selective mu opioid, DAMGO. At the doses and injection routes used, nor-BNI itself had no apparent effect on overt behavior or MES-induced convulsions. These data support the earlier suggestion that the anticonvulsant effects of U50,488 are mediated by kappa opioid receptors and confirm 1) the selectivity of nor-BNI as a kappa antagonist and 2) its applicability as a pharmacological tool in the differentiation of multiple opioid receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗