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Biomedical subjects

A E Takemori

Publications and source records attributed to A E Takemori.

At least 37 records · Page 2Linked to original sources
PubMed1993

3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines: opioid antagonists with potent anorectant activity.

A series of (3R*,4R*)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists with varying substituents on the nitrogen were evaluated for their effect on food consumption in obese Zucker rats. Opioid affinity (mu, kappa, and delta for selected compounds) and opioid antagonist activity (mu and kappa) were characterized and compared to effects on food consumption. No compounds with high selectivity for either mu or kappa receptors were discovered. However, compounds in the series had exceptional potency as opioid antagonists and in reducing food consumption in the obese Zucker rat. In contrast, a few compounds with high potency as opioid antagonists had much weaker potency for inhibiting food consumption. (3R,4R)-3,4-Dimethyl-1-[(3S)-3- hydroxy-3-cyclohexyl-propyl]-4-(3-hydroxyphenyl)piperidine (11,LY255582) emerged as having the best activity profile, both in reducing food consumption and as an opioid antagonist. Compound 11 is a highly potent mu, kappa-, and delta-opioid antagonist with possible clinical utility as an appetite suppressant for weight loss.

Analgesia↗
PubMed1993

Enkephalin antinociception in mice is mediated by delta 1- and delta 2-opioid receptors in the brain and spinal cord, respectively.

Pharmacological evidence for the existence of delta-opioid receptor subtypes has been reported. This study was conducted to determine which type of delta-opioid receptors was involved supraspinally and spinally when antinociception was induced by the natural enkephalins, [Leu5]enkephalin and [Met5]enkephalin. In the mouse tail flick assay, the antinociceptive ED50 values of both intracerebroventricularly (i.c.v.) administered [Leu5]enkephalin and [Met5]enkephalin (together with the peptidase inhibitors, bestatin and thiorphan) were significantly increased by 7-benzylidenenaltrexone (BNTX), a selective delta 1-opioid receptor antagonist but not by naltriben, a selective delta 2-opioid receptor antagonist. On the other hand, when the enkephalins were administered intrathecally (i.t.), the antinociceptive ED50 values of both enkephalins were significantly raised by naltriben but not by BNTX. beta-Endorphin-induced (i.c.v.) antinociception was antagonized by naltriben administered i.t. or s.c. but not by BNTX administered i.t. or s.c. Different delta-opioid receptor subtypes appeared to be involved in supraspinal (delta 1) and spinal (delta 2) antinociception induced by endogenous delta-opioid receptor agonists, [Leu5] and [Met5]enkephalin. The antinociception produced by i.c.v. administered beta-endorphin has been attributed to the release of [Met5]enkephalin in the spinal cord and its antagonism by naltriben support the finding that enkephalins interact with delta 2-opioid receptors in the spinal cord to mediate antinociception. beta-Endorphin may be interacting at receptors other than delta 1- or delta 2-opioid receptors in the brain, perhaps the putative epsilon receptors, to mediate their effects because neither i.c.v. administered BNTX nor naltriben inhibited its activity.

Animals↗
PubMed1993

Synthesis and kappa-opioid antagonist selectivity of a norbinaltorphimine congener. Identification of the address moiety required for kappa-antagonist activity.

Compound 2, which represents a structurally simplified congener of norbinaltorphimine 1a, was synthesized in order to evaluate the role of its second basic nitrogen in conferring kappa-opioid receptor antagonist selectivity. Congener 2 was found to be at least twice as selective as 1a as a kappa antagonist, while its N-carbobenzoxy derivative (3) was inactive at kappa-receptors. This study establishes the importance of the second basic nitrogen of 1a for kappa-receptor recognition. It is proposed that this basic group mimics the guanidinium moiety of Arg7, which may be the key kappa-address component of dynorphin.

Animals↗
PubMed1993

Differential antagonism by naltrindole-5'-isothiocyanate on [3H]DSLET and [3H]DPDPE binding to striatal slices of mice.

Naltrindole-5'-isothiocyanate (5'-NTII), a nonequilibrium delta opioid receptor antagonist, has been shown to antagonize differentially the antinociception induced by DSLET without affecting that induced by DPDPE. In the present study, we investigated whether or not 5'-NTII can differentially affect DSLET and DPDPE binding to receptor sites in striatal slices of mouse brain. We found that 5'-NTII only changed the binding characteristics of [3H]DSLET and not that of [3H]DPDPE. Saturation binding studies revealed that 5'-NTII treatment in vitro inhibited [3H]DSLET binding by decreasing the affinity but not the number of binding sites. This finding was supported by saturation studies with [3H]DSLET in striatal slices from mice that were pretreated with 5'-NTII (10 nmol, i.c.v. or 10 mg/kg, s.c.). Thus, the results suggest that 5'-NTII can antagonize differentially the binding to striatal slices of mice of [3H]DSLET but not that of [3H]DPDPE. The binding parameters also suggest that 5'-NTII may not antagonize [3H]DSLET binding by alkylating at the receptor recognition site because the number of binding sites did not decrease. 5'-NTII may bind to some other part of the membrane to indirectly desensitize the receptor to a low affinity form. Lastly, the differential alteration of binding sites between [3H]DSLET and [3H]DPDPE by 5'-NTII strongly support the postulated existence of delta opioid receptor subtypes.

Analgesics↗
PubMed1993

Relative involvement of supraspinal and spinal mu opioid receptors in morphine dependence in mice.

Involvement of supraspinal and spinal mu opioid receptors in the development degree of morphine dependence was estimated by the ED50 values of naloxone (s.c.) required to precipitate withdrawal jumping and diarrhea 72 hr after morphine-pellet implantation. beta-FNA was administered 4 times (24 hr before, just before, 24 and 48 hr after morphine-pellet implantation) by the i.c.v. or i.t. route. beta-FNA (both i.c.v. and i.t. routes) significantly increased the ED50 values of naloxone for jumping and diarrhea and the increase in the ED50 value of naloxone for jumping was much greater than that for diarrhea. I.c.v. administered beta-FNA was more potent in increasing the ED50 value of naloxone for jumping than i.t. administered beta-FNA. On the other hand, i.c.v. administered beta-FNA was equipotent with i.t. administered beta-FNA in increasing the ED50 value of naloxone for diarrhea. These results suggest that both supraspinal and spinal mu opioid receptors are involved in the development of morphine dependence and that supraspinal mu receptors play a more important role than spinal mu receptors in withdrawal jumping which may reflect an excitation of the central nervous system whereas supraspinal and spinal mu receptors have similar importance in withdrawal diarrhea which may reflect an abnormal function of the autonomic nervous system.

Animals↗
PubMed1993

7-Benzylidenenaltrexone (BNTX): a selective delta 1 opioid receptor antagonist in the mouse spinal cord.

Recent reports provided evidence that at least two delta opioid receptors may mediate antinociception in mice. In this study, we studied further the involvement of delta opioid receptor subtypes in mediating antinociception at spinal sites in mice using subtype selective agonists and antagonists. The antinociceptive ED50 values (95% C.I.) of i.t. administered DPDPE [(D-Pen2, D-Pen5)enkephalin] (delta 1 receptor agonist) and DELT II [(D-Ala2)deltorphin II] (delta 2 receptor agonist) were 6.3 (5.2-7.6) and 6.4 (5.4-7.7) nmol/mouse, respectively. Administration of BNTX, s.c. increased the antinociceptive ED50 value of DPDPE 5.9-fold whereas that of DELT II was not changed significantly. On the other hand administration of naltriben (NTB, the benzofuran derivative of naltrindole), s.c. increased the antinociceptive ED50 value of DELT II 12.5-fold but did not alter that of DPDPE. Similarly administration of BNTX, i.t. increased the antinociceptive ED50 value of DPDPE 4-fold without altering significantly that of DELT II. NTB given i.t. enlarged the antinociceptive ED50 of DELT II 11-fold without affecting significantly that of DPDPE. BNTX, s.c. did not alter the antinociceptive ED50 values of the mu-agonists, DAMGO [(D-Ala2,MePhe4,Gly-ol5) enkephalin] and morphine or that of the kappa-agonist, U50,488H [trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl-cyclohexyl]benzeneacetamide] These results demonstrate that BNTX is highly selective for delta 1 opioid receptors at spinal sites. Also, the present data provide for the involvement of both delta 1 and delta 2 opioid receptors in mediating antinociception at spinal sites in mice.

Analgesics↗
PubMed1993

The mixed antinociceptive agonist-antagonist activity of beta-endorphin(1-27) in mice.

beta-Endorphin(1-27) (i.c.v.) has been reported to inhibit the antinociceptive activity of i.c.v. administered beta-endorphin in mice. In this study the antagonist activity of beta-endorphin(1-27) has been confirmed and the antagonism appears to be mediated at delta 1 opioid receptors. At higher doses than that used for antagonism, i.c.v. administered beta-endorphin(1-27) was a full antinociceptive agonist. The antinociceptive activity of beta-endorphin is attributed to the release of met-enkephalin in the spinal cord and is antagonized by the selective delta 2 opioid receptor antagonist, naltriben (NTB) but not by the selective delta 1 opioid receptor antagonist, 7-benzylidenenaltrexone (BNTX). In contrast, the antinociceptive activity of i.c.v. administered beta-endorphin(1-27) was not affected by either NTB or BNTX administered i.c.v. or i.t. Also, the antinociceptive activity of beta-endorphin(1-27) was unaffected by the selective mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA) or the selective kappa opioid receptor antagonist, norbinaltorphimine (norBNI). Thus, beta-endorphin(1-27) appears to mediate antinociception supraspinally through the interaction of a unique receptor, i.e. a receptor that is different from mu, kappa, delta 1 or delta 2 opioid receptors. Alternatively, a non-opioid mechanism may be considered.

Animals↗
PubMed1993

Inhibition of naloxone-precipitated withdrawal jumping by i.c.v. and i.t. administration of saline in morphine-dependent mice.

In morphine-dependent mice, s.c. and i.t. administered naloxone produced withdrawal jumping (ED50 values were i.t. = s.c.) but i.c.v. administered naloxone failed to produce dose-dependent jumping. Peak times of jumping were earliest after i.t. administration of naloxone among the three administration routes. These results suggested that the spinal site was more sensitive to naloxone than the supraspinal site. Concomitant administration of naloxone i.c.v. and i.t. did not precipitate jumping. It was found that i.c.v. and i.t. injections of saline inhibited withdrawal jumping precipitated by s.c. administered naloxone and that the i.c.v. effect was more profound than the i.t. effect. I.c.v. injection of saline also delayed the peak time of withdrawal jumping precipitated by s.c. administered naloxone. These inhibitory effects of the injection procedures may explain the difficulty of i.c.v. administered naloxone and concomitant i.c.v. + i.t. administered naloxone to precipitate jumping, and may explain the difference in the ED50 values of naloxone and the time courses of jumping.

Animals↗
PubMed1993

Sites of action of naloxone in precipitating withdrawal jumping in morphine-dependent mice: investigations by the ED50 value and CNS content of naloxone.

The sites of action of naloxone and the possible interaction between supraspinally and spinally administered naloxone in precipitating withdrawal jumping were investigated by comparing the ED50 value and central nervous system (CNS) content of naloxone after three different administration routes in morphine-dependent mice. ED50 values of naloxone for i.c.v., i.t. and s.c. routes were 18.8 nmol, 1.95 nmol and 50.6 nmol/kg, respectively. Jumping occurred most often within 5 min after i.t administered naloxone, but it took more than 10 min to reach the most frequent jumping after s.c. and i.c.v. administered naloxone. After equi-effective doses (ED50) of naloxone were administered i.c.v., i.t. or s.c., the content of naloxone in the brain was 70 times lower after s.c. than that after i.c.v. injection. The concentration of naloxone in the spinal cord was 37 times lower after s.c. than that after i.t. injection. The ED50 values of naloxone and the time courses of jumping suggest that spinal sites appear to be more important than the supraspinal sites and comparisons of naloxone-content suggest that there is a synergistic interaction between supraspinal- and spinal-naloxone after systemic administration.

Animals↗
PubMed1993

Suppression by dynorphin A and [des-Tyr1]dynorphin A peptides of the expression of opiate withdrawal and tolerance in morphine-dependent mice.

Previously, we demonstrated that the expression of opiate withdrawal and antinociceptive tolerance can be suppressed by dynorphin (dyn) A-(1-13) in morphine-dependent mice. In this study, it was shown that the normal, endogenous dyn, dyn A-(1-17) also possessed this suppressive property. While using the nonopioid dyn analog, [des-Tyr1]dyn A [dyn A-(2-17)] as a negative control, we discovered unexpectedly that this peptide fragment also suppressed naloxone-induced withdrawal and the expression of morphine tolerance in morphine-dependent mice. Thus, an extensive structure activity relationship was studied using 11 peptide fragments. It was determined that the amino acid sequence of dyn A was required for the suppressive activity because dyn B and alpha-neoendorphin both failed to suppress naloxone-precipitated withdrawal jumping. Of the [des-Tyr1]dyn fragments, the minimal amino acid sequence required to suppress naloxone-induced withdrawal was determined to be dyn A-(2-8), containing the sequence G-G-F-L-R-R-I.

Amino Acid Sequence↗
PubMed1993

Modulation of morphine antinociception by swim-stress in the mouse: involvement of supraspinal opioid delta-2 receptors.

The present study evaluated the effect of a brief exposure of mice to cold-water swim-stress (CWSS) on the antinociceptive potency of i.c.v. given morphine. No significant antinociceptive response could be demonstrated in the warm-water tail-flick test, 10 min after a 30-sec exposure of mice to water at 5 degrees C. However, the i.c.v. morphine dose-response curve in mice exposed to CWSS was displaced significantly to the left when compared to that obtained in control (i.e., non-CWSS-exposed) mice. Although coadministration of the delta antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH 1 (ICI 174,864), with i.c.v. morphine did not produce antagonism of the antinociceptive action of this mu opiate, the leftward displacement of the i.c.v. morphine dose-response curve seen in CWSS-exposed mice was blocked in ICI 174,864-treated mice suggesting involvement of opioid delta receptors in the modulatory effect. Pretreatment of mice with the delta-1 antagonist, [D-Ala2, Leu5, Cys6] enkephalin, did not antagonize the antinociception of morphine and further did not antagonize the leftward displacement produced by exposure to CWSS. Pretreatment of mice with the delta-2 antagonist, 5'-isothiocyanate, also did not antagonize the antinociceptive effects of morphine but blocked the leftward displacement in the morphine dose-response curve associated with CWSS, suggesting involvement of an opioid delta-2 receptor in this effect. Pretreatment of mice with the mu antagonist, beta-funaltrexamine, produced a significant antagonism of the morphine antinociceptive effect as seen by a rightward displacement of the morphine dose-effect curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Evidence for a single functional opioid delta receptor subtype in the mouse isolated vas deferens.

The identification of opioid delta receptor subtypes in mouse brain led to the investigation of the nature of the opioid delta receptors in the mouse isolated vas deferens in vitro. Noncumulative concentration-effect curves were constructed for DPDPE (delta 1 agonist) and [D-Ala2, Glu4]deltorphin (delta 2 agonist) in control tissues, or in tissues which had been incubated with either [D-Ala2, Leu5, Cys6] enkephalin (DALCE) (noncompetitive delta 1 antagonist) or 5'-naltrindole isothiocyanate (5'-NTII) (noncompetitive delta 2 antagonist). Incubation of the tissues with DALCE, under either oxygenated or nonoxygenated conditions, did not alter the concentration-effect curves for either agonist. In contrast, incubation of the tissues with 5'-NTII resulted in a significant rightward displacement of the concentration-effect curves of both DPDPE and [D-Ala2, Glu4] deltorphin. Additionally, naltriben, a selective and competitive delta 2 antagonist, showed no significant difference in its ability to antagonize a fixed, submaximal concentration of either DPDPE or [D-Ala2, Glu4]deltorphin. Furthermore, there was no significant difference in the affinity of naloxone (i.e., pA2) at the receptor(s) acted upon by either DPDPE or [D-Ala2, Glu4]deltorphin. Tolerance to DPDPE or [D-Ala2, Glu4]deltorphin was produced by incubation of the tissues with these agonists; construction of the [D-Ala2, Glu4]deltorphin concentration-effect curve in DPDPE-tolerant tissues demonstrated cross-tolerance between these agonists and, conversely, construction of DPDPE concentration-effect curves in [D-Ala2, Glu4]deltorphin-tolerant tissues revealed cross-tolerance between these agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Involvement of delta 2 opioid receptors in the development of morphine dependence in mice.

The possible involvement of delta 2 opioid receptors in the development of morphine dependence was investigated using selective delta 2 receptor antagonists, naltriben (NTB) and naltrindole 5'-isothiocyanate (5'-NTII). The degree of morphine dependence was estimated by the ED50 values of naloxone (s.c.) required to precipitate withdrawal jumping and diarrhea 72 hr after morphine pellet implantation. NTB administered s.c. as well as naloxone precipitated jumping and diarrhea in morphine-dependent mice. Chronic treatment with 5'-NTII (both i.c.v. and i.t. routes, 24 hr before, just before, 24 and 48 hr after morphine pellet implantation) increased the ED50 values of naloxone for jumping and diarrhea. These results suggest that both supraspinal and spinal delta 2 opioid receptors are involved in the development of physical dependence on systemically administered morphine. However, chronic treatment with NTB (s.c. route, 30 min before, 24 and 48 hr after morphine pellet implantation) failed to affect the ED50 values of naloxone for both withdrawal signs. These seemingly discrepant results suggest that continuous blockade of delta 2 opioid receptors (by a nonequilibrium and long-lasting antagonist, 5'-NTII) rather than intermittent blockade of delta 2 opioid receptors (by an equilibrium and relatively short-acting antagonist, NTB) is necessary to inhibit the development of morphine dependence.

Animals↗
PubMed1993

Effect of antagonists selective for mu, delta and kappa opioid receptors on the reinforcing effects of heroin in rats.

Antagonists selective for mu, delta and kappa-opioid receptors were evaluated for their effects on responding maintained by i.v. injections of heroin (60.0 micrograms/kg/injection) in rats during daily 3-hr sessions. Under base-line conditions, rats self-administered 10 to 20 heroin injections during each session, and injections were separated by relatively constant interinjection intervals of about 10 to 20 min. The mu-selective antagonist beta-funaltrexamine (beta-FNA; 5.0-20.0 mg/kg, s.c.) produced a dose-dependent increase in responding for heroin, with some doses of beta-FNA producing an extinction-like pattern of responding. These results were qualitatively similar to the effect obtained by lowering the unit dose per injection of heroin. The mu 1-selective antagonist naloxonazine (NXZ; 7.5-30.0 mg/kg, i.v.) and the delta-selective antagonist naltrindole (1.0-17.0 mg/kg) also produced dose-dependent increases in heroin self-administration, but neither naloxonazine nor naltrindole produced extinction-like patterns of responding. The kappa-selective antagonist nor-binaltorphimine (nor-BNI; 5.0-10.0 mg/kg, s.c.) had no effect on heroin self-administration. These results indicate that mu receptors play an important role in mediating the reinforcing effects of heroin in the rat. Delta and mu 1 receptors, but not kappa receptors, may also be involved.

Animals↗
PubMed1993

Involvement of delta 2 opioid receptors in acute dependence on morphine in mice.

The effects that naltriben (NTB) and naltrindole 5'-isothiocyanate (5'-NTII) have on acute morphine dependence were investigated in mice. The degree of acute dependence was estimated by the ED50 value of s.c.-administered naloxone that was required to precipitate withdrawal jumping 4 hr after s.c. injection of 100 mg/kg of morphine sulfate (MS-100). Pretreatments with NTB (10 mumol/kg, s.c., 30 min before MS-100) and 5'-NTII (10 mumol/kg, s.c., 24 hr before MS-100) increased the ED50 values of naloxone compared to those of the respective saline-treated control mice. Although NTB itself (up to 10 mumol/kg s.c.) did not precipitate jumping 4 hr after MS-100, small doses of NTB (1 and 2 mumol/kg, s.c.) administered 30 min before the challenge doses of naloxone increased substantially the ED50 value of naloxone. These results suggest that delta 2 opioid receptors are involved in acute dependence on morphine in mice.

Animals↗
PubMed1992

Opioid agonist and antagonist activities of morphindoles related to naltrindole.

A series of naltrindole-related ligands (4-10) with an N-methyl,N-phenethyl,N-cinnamyl, or an unsubstituted basic nitrogen were synthesized and tested for opioid agonist and antagonist activity in smooth muscle preparations and in mice. The nor compounds (4 and 6) and the phenethyl derivatives (5 and 8) displayed full agonist activity (IC50 = 85-179 nM) in the mouse vas deferens preparation (MVD) while the other members of the series exhibited partial agonist or weak antagonist activity. In the guinea pig ileum preparation (GPI), all compounds except 8 were partial agonists. The ligands that were evaluated in mice were found to produce antinociception that was not selectively mediated via delta opioid receptors. However, two of these ligands (4 and 5) appeared to be delta-selective opioid receptor antagonists at subthreshold doses for antinociception. The finding that all of the compounds bind selectively to delta opioid receptors in guinea pig brain membranes together with the in vitro pharmacology and in vivo antagonist studies suggests that the lack of delta agonist selectivity in vivo may be due to a number of factors, including a basic difference between the delta receptor system in the MVD and in the mouse brain. Further, it is suggested that the constellation of message and address components in the morphindole nucleus may tend to stabilize delta receptors in the brain in antagonist state.

Analgesia↗