Guinea Pig Ileum Preparations Research Articles

The guinea-pig ileum preparation as a model for 5-HT1A receptors: anomalous effects with RS-30199-193

1. Agents that have high and selective affinity for the 5-HT1A site such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and N,N-dipropyl-5-carboxamidotryptamine (DP5CT) inhibited the responses to field stimulation in guinea-pig ileum preparations; the inhibitory effects were antagonized by methiothepin and spiperone, consistent with effects at the 5-HT1A site. 2. The inhibitory effects of DP5CT were pronounced in Tyrode solution containing low Ca2+ (0.9 mM), but were much less apparent in Tyrode solution containing 1.8 or 5.4 mM Ca2+. 3. Responses to DP5CT were abolished by pretreatment with phorbol dibutyrate (3 microM), whereas the responses to UK14304 were only slightly inhibited. 4. Buspirone and ipsapirone (1 microM) inhibited the responses to field stimulation, and the effects were resistant to idazoxan, but inhibited by 8-OH-DPAT or spiperone. 5. RS-30199-193 (5-chloro-2-methyl-1,2,3,4,8,9,10,10a-octahydronaphth-[1,8-cd]- aze pine hydrochloride) an azepine with high affinity for the 5-HT1A site in rat cerebral cortex in binding experiments, augmented contractions, but did not antagonize the responses to DP5CT or to 8-OH-DPAT. 6. The hybrid compound of RS-30199-193 with buspirone, RS-64459-193 (5-chloro-2-[4-(8-azaspiro[4,5]decane-7,9-dione)-but-1-yl]- 1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]-3-azepine hydrochloride) maintained high affinity for the 5-HT1A binding site in rat brain and both inhibited the response to field stimulation and antagonized the responses to 8-OH-DPAT and DP5CT. Thus the buspirone side chain when added to RS-30199-193 appears either to induce affinity for a distinct subset of receptors in the guinea-pig ileum or is required for functional effectiveness at the 5-HTlA receptor.

Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies.

1. Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) is a new bradykinin (BK)-antagonist. It was tested in several in vitro assays and compared with D-Arg-[Hyp2,Thi5,8,D-Phe7]BK. 2. In receptor binding studies in guinea-pig ileum preparations, Hoe 140 showed an IC50 of 1.07 x 10(-9) mol l-1 and a KI value of 7.98 x 10(-10) mol l-1. 3. In isolated organ preparations Hoe 140 and D-Arg-[Hyp2,Thi5,8, D-Phe7]BK inhibited bradykinin-induced contractions concentration dependently, with IC50-values in the guinea-pig ileum preparation of 1.1 x 10(-8) mol l-1 and 3 x 10(-5) mol l-1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 x 10(-9) mol l-1 for Hoe 140. D-Arg-[Hyp2, Thi5,8, D-Phe7]BK showed an IC50 of 4.0 x 10(-6) mol l-1. The IC50 values in the guinea-pig isolated pulmonary artery were 5.4 x 10(-9) mol l-1 and 6.4 x 10(-6) mol l-1, respectively. In the rabbit aorta no inhibitory effects on Des-Arg9-BK induced contractions were observed. 4. In cultured bovine endothelial cells, Hoe 140 antagonized (IC50 = 10(-8) mol l-1) bradykinin-induced endothelium-derived relaxing factor (EDRF) release and the bradykinin-induced increase in cytosolic free calcium (IC50 = 10(-9) mol l-1). 5. Hoe 140 (10 -7mol I1) totally suppressed the bradykinin-induced (10 8 to 10- mol I') prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. D-Arg-[Hyp2, Thi5'8, D-Phe7]BK (10- 7 mol I1- ) showed a weaker antagonism. 6. Taken together these results show that Hoe 140 is a highly potent bradykinin antagonist. It was two to three orders of magnitude more potent than D-Arg-[Hyp2, Thi5 8, D-Phe7]BK.

Novel selective agonists and antagonists confirm neurokinin NK1 receptors in guinea‐pig vas deferens

1. This study investigated the recognition characteristics of neurokinin receptors mediating potentiation of the contractile response to field stimulation in the guinea-pig vas deferens. 2. A predominant NK1 receptor population is strongly suggested by the relative activities of the common naturally-occurring tachykinin agonists, which fall within less than one order of magnitude. This conclusion is supported by the relative activities of the synthetic NK1 selective agonists substance P methyl ester, [Glp6,L-Pro9]-SP(6-11) and delta-aminovaleryl-[L-Pro9,N-MeLeu10]- SP(7-11) (GR73632) which were 0.78, 9.3 and 120 as active as substance P, respectively. Furthermore, the NK2 selective agonist [Lys3, Gly8,-R-gamma-lactam-Leu9]-NKA(3-10) (GR64349) was active only at the highest concentrations tested (greater than 10 microM), and the NK3 selective agonist, succ-[Asp6,N-MePhe8]-SP(6-11) (senktide) was essentially inactive (10 nM-32 microM). 3. [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-SP(1-11) antagonized responses to neurokinin A, neurokinin B, physalaemin, eledoisin, [Glp6,D-Pro9]-SP(6-11), GR73632 and GR64349 (apparent pKB s 5.6-6.2), but was less potent in antagonizing responses to substance P, substance P methyl ester and [Glp6,L-Pro9]-SP(6-11) (apparent pKB s less than or equal to 5.0-5.0). 4. In contrast, the recently developed NK1-selective receptor antagonist [D-Pro9[Spiro-gamma-lactam]Leu10,Trp11]-SP(1-11) (GR71251) did not produce agonist-dependent pKB estimates. Schild plot analysis indicated a competitive interaction with a single receptor population where the antagonist had an estimated overall pKB of 7.58 +/- 0.13 for the four agonists of differing subtype selectivity tested (GR73632, GR64349, substance P methyl ester and neurokinin B). This estimate is similar to that we obtained for NK1-mediated (substance P methyl ester) contraction in the guinea-pig ileum preparation (pKB= 7.86+ 0.05). 5. Tachykinin action appears not to depend on release of a number of intermediary mediators including acetylcholine, histamine or cyclo-oxygenase products, nor to involve interaction with neuronal mechanisms including alpha 2-adrenoceptor feedback, noradrenergic Uptake-I or opioid-release, since antagonism or inhibition of these mechanisms did not modify responses to tachykinins. 6. We conclude that tachykinin action in the field-stimulated guinea-pig vas deferens preparation is mediated through interaction with a predominant neurokinin NK, receptor population and this preparation can therefore be used to study NK, modulation of sympathetic neurotransmission.

Delta opioid receptor-selective ligands: [ ] enkephalin-dermenkephalin-dermenkephalin chimeric peptides

A number of DPDPE-dermenkephalin chimeric peptides have been synthesized in which the putative C-terminal delta-address of dermenkephalin has been linked to the highly delta opioid selective cyclic peptide ▪ enkephalin (DPDPE). Asp, Met-Asp and Leu-Met-Asp have been added to the C-terminus of DPDPE and both the carboxyl terminal and the carboxamide terminal series have been prepared. The bioassays using the mouse vas deferens and guinea pig ileum preparations have revealed a steady decrease in potency (compared to DPDPE) at delta and mu receptors as the dermenkephalin sequences were added. Some of the analogues, however, retained high delta selectivity. Similar results were obtained using radioligand binding assays. These findings suggest that the C-terminal amino acid sequence of dermenkephalin plays a role of delta-address which is specific to dermenkephalin itself, and is not additive with another delta selective ligand such as DPDPE.

Enantiomers of 11‐hydroxy‐10‐methylaporphine having opposing pharmacological effects at 5‐HT1A receptors

The two enantiomers of the title compound have been prepared by different synthetic routes. Both bind strongly to 5-HT1A receptors from rat forebrain membrane tissue. However, in a guinea pig ileum preparation, the (R)-enantiomer exhibits properties consistent with its being an agonist, whereas the (S)-enantiomer shows no agonist effect, but it blocks the actions of the (R)-enantiomer and of 8-hydroxy-2-di-n-propylaminotetralin (8-OH-DPAT), a 5-HT1A agonist. These data are presented as a rare example of enantiomers which demonstrate opposite pharmacological effects at the same receptor.

Synthesis of 20-alkyl-8-thiathevinols, opiate agonists derived from 8-thiathevinone, the cycloadduct of thebaine and 2-oxopropanethial

The cycloadduct 7 has been prepared from thebaine 1 and the transient thioaldehyde EtO2C–CH2S formed in situ from the Bunte salt EtO2C–CH2SSO3Na. The thermal isomerisation of the adduct 7 to give the regioisomer 8 has been reinvestigated. Prolonged heating gave an equilibrium mixture of the adduct 8 and the major, rearrangement product 9. Base-catalysed epimerisation of the adduct 7 gave the 7β-isomer 11, believed to be a transient co-product in the thermal isomerisation of the original adduct 7. Similarly, thebaine 1 and 2-oxopropanethial 18, generated from either the Bunte salt McCOCH2SSO3Na or the thiotosylate 16 and triethylamine, gave the cycloadduct 8-thiathevinone 3, the sulphur analogue of thevinone 2, the known cycloadduct of thebaine and but-3-en-2-one. 8-Thiathevinone 3 isomerised thermally to give the corresponding, 7-thia regioisomer.8-Thiathevinone 3 has been converted with Grignard reagents into a series of (20R)-and (20S)20-alkyl-8-thiathevinols 5. The reactions were not stereoselective, unlike those of thevinone 2, and the tertiary alcohols 5 were accompanied by the secondary alcohols 19 and 20, products of ‘Grignard reduction’. The analgesic potency, in guinea-pig ileum preparations, of the alkylthiathevinols 5 depended upon the C-20 configuration and the alkyl chain length. The (20R)-epimers were the more potent, the maximum potency being observed for the (20R)-20-pentyl derivative 5h, which was equipotant with N-normorphine. Generally, the thiathevinols were much less potent than the corresponding thevinols. 8-Thiathevinone 3 also reacted with alkyllithium reagents to give (20R)-alkylthiathevinols, but the reactions were accompanied by a base-catalysed rearrangement to give the ketoacetal 27.

The opioid activity and receptor selectivity of fluorinated Leu5 Enkephalin analogues in vitro and in vivo.

The opioid activity and the selectivity for opioid receptor (subtypes) of newly synthesized fluorinated enkephalin (Enk) analogues, [2R, 4R], [2R, 4S], [2S, 4S] and [2S, 4R] trifluoro-Leu5-Enk (KKF-31, 32, 33 and 34) were investigated. The inhibitory effect of KKF-compounds on the electrically induced contractions of guinea-pig ileum (GPI) and mouse vas deferens (MVD) were dose-dependent but relatively lower than that of L-Leu5-Enk, except that KKF-34 was rather slightly more potent than L-Leu5-Enk in MVD preparations. In GPI preparations, the pA2 values of naloxone for these compounds were higher than those of naltrindole while the values of naltrindole for KKF-compound were higher than those of naloxone in MVD preparations. Intracerebroventricular KKF-31 and KKF-32 at doses of 20 and 10 nmol/mouse, respectively, produced analgesia comparable to 0.1 nmol Tyr-D-Arg-Phe-Lys-NH2 and 100 nmol Tyr-D-Thr-Gly-Phe-Leu-Thr; however, neither KKF-33 nor 34 produced analgesia up to the doses of 100 nmol/mouse. Both naloxone, 1 mg/kg, i.p., and naltrindole, 10 mg/kg, i.p., antagonized KKF-31- and KKF-32-induced analgesia. The results suggest that the introduction of trifluoromethyl group in Leu5 results in the alternation of the opioid activity and receptor selectivity. Although KKF-33 and KKF-34 possessed a more potent in vitro inhibitory effect than KKF-31 and KKF-32, mediated through mu- and delta-opioid receptors in both preparations, they did not show any appreciable analgesic effect. KKF-31 and KKF-32 produce naloxone- and naltrindole-reversible analgesia irrespective of in vitro mu- and delta-opioid activity.

The action of dexamethasone on electrically-induced contractions of guinea-pig isolated ileum

1. 1. The effect of dexamethasone and its interaction with morphine has been studied on transmurally-stimulated guinea-pig ileum preparation. 2. 2. Dexamethasone dose-dependently depressed the contractions of the ileum; this action has a rapid onset. 3. 3. Naloxone did not reverse the inhibitory effect of dexamethasone. 4. 4. When dexamethasone and morphine were given in combination the maximum reduction observed was equal to the sum of the single effect of two drugs given individually and naloxone antagonized only the inhibition induced by morphine. 5. 5. Proteic synthesis inhibitors did not modify the inhibition induced by dexamethasone. 6. 6. RU-38486, a glucocorticoid antagonist receptor, antagonized completely the inhibitory effect of DXM without affecting the inhibition induced by morphine showing that the effect of dexamethasone occurs by glucocorticoid receptors-mediated processes.

Inhibition of electrically evoked contractions of guinea-pig ileum preparations mediated by the histamine H 3 receptor

We investigated the contraction responses of isolated guinea-pig ileum preparations under several conditions of electrical field stimulation. Histamine H 3-agonists caused a dose-dependent inhibition of both cholinergic and nonadrenergic noncholinergic (NANC) responses (pD 2 of histamine, 7.3; N α-methylhistamine, 8.4; (R)-α-methylhistamine, 8.3); H 3-antagonists blocked this inhibition (pA 2 of impromidine, 7.2; thioperamide, 8.5). Our results indicate that H 3-receptors are present on both cholinergic and NANC nerves in the myenteric plexus and that the preparation can be used as a rapid and simple test system for histamine H 3-receptors.

Synthesis and biological evaluation of 14-alkoxymorphinans. 3. Extensive study on cyprodime-related compounds

A series of cyprodime-related compounds (2, 4-12, and 26) has been synthesized and evaluated for opioid agonist and antagonist activity with the mouse vas deferens and guinea pig ileum preparations. None of the changes to cyprodime, including the introduction of a 3-OMe group, increasing and decreasing the size of or completely removing the substituent in position 4, replacing the N-cyclopropylmethyl group with an N-allyl group, or replacing the 14-OMe with an 14-OEt substituent, resulted in an improved mu antagonist profile and most were detrimental either in terms of mu selectivity and potency or increased agonist activity. Increasing the length of the substituent in position 4 resulted in a compound (6a) with a very similar profile to that of cyprodime.

Some pharmacological characteristics of the guinea pig ileum opioid system activated by cholecystokinin

Naloxone, added after contractions induced by CCK-8 on the guinea pig ileum preparation, elicited a contraction attributed to the release of endogenous opioid which could inhibit the excitatory action of the peptide. With large concentrations of CCK-8, the preparation gave reproducible responses with time. Naloxone, added before the peptide, protracted the excitatory response to CCK-8, but not its height. Morphine decreased the response to CCK-8 but simultaneously raised the response to naloxone. The latter effect appeared very similar to the withdrawal contraction observed after brief exposure of the opioid in the guinea pig ileum to opioids. Clonidine, and alpha-2 adrenoceptor agonist, and nifedipine, a calcium channel antagonist, both known to interfere with tolerance and physical dependence, affected the excitatory response to CCK-8 and the subsequent response to naloxone in a different way.

Use of an isolated guinea-pig ileum assay to detect bioactive compounds in microalgal cultures

An isolated guinea-pig ileum preparation was used to screen for bioactive compounds from algae. 212 culture supernatants and methanolic extracts of randomly chosen marine and freshwater algae were tested for their effect on electrically evoked muscle contractions (recorded as a change in tension) and on the resting muscle tone. 15 out of 42 (35%) of the marine algae tested and 5 out of 64 (8%) of freshwater algae gave positive results. Of the 20 algae giving positive results, 6 had previously been shown to produce bioactive compounds (mainly toxins) but we can find no reports in the literature of bioactive compounds from the remaining 14. Of these 14 cultures, 9 were axenic and therefore production of the biological activity can be assigned unambiguously to the alga. These results confirm the usefulness of the guinea-pig ileum preparation as a screen for bioactive compounds from microbial cultures.

The opioid receptor selectivity for trimebutine in isolated tissues experiments and receptor binding studies.

Differences of affinity to and selectivity for trimebutine between peripheral and central opioid receptors have been investigated. Trimebutine inhibited electrically induced contraction of guinea-pig ileum (GPI) and mouse vas deferens (MVD) but not of rabbit vas deferens, and the inhibition was antagonized by naloxone and, to lesser extent, by nor-binaltorphimine (nor-BNI). The pA2 values for morphine and trimebutine with naloxone were higher than the values for these compounds with nor-BNI in both GPI and MVD preparations. GPI preparations incubated with a high concentration of morphine or trimebutine developed tolerance; however, there was no cross-tolerance between them, suggesting difference in the underlying mechanisms. In mouse and guinea-pig brain homogenate trimebutine was about 1/13 as potent as morphine to displace the [3H]naloxone binding, while it has no appreciable affinity for kappa-opioid receptors in [3H]U-69593, a selective kappa-receptor agonist. These results suggest that trimebutine, showing its low affinity to opioid receptors, possesses mu-receptor selective properties rather than those of kappa-opioid receptor in the peripheral tissues and in the central brain homogenate.

中枢性鎮痛薬Ｅｐｔａｚｏｃｉｎｅのモルモット回腸，マウス輸精管標本におけるオピオイド受容体サブタイプ選択的作用

Actions of eptazocine, a novel analgesic, on isolated smooth muscle preparations were investigated. Eptazocine (10(-5) M) slightly inhibited electrically-driven twitch-tension in guinea pig ileum preparations sensitive to mu- and kappa-agonists, and this effect was antagonized by 10(-7) M naloxone. Eptazocine (10(-5)-10(-4) M) inhibited such an effect by the mu-agonist morphine. In mouse vas deferens preparations having delta-, mu- and kappa-receptors, eptazocine (10(-7) M-) inhibited the twitch-tension in a dose-dependent manner, being hardly inhibited by naloxone. On the other hand, MR-2266 (10(-6) M), a relatively selective kappa-receptor antagonist, inhibited the eptazocine effect. The Ke (equilibrium dissociation constant) value of naloxone against eptazocine was 325 nM and the Ke value of MR-2266 against eptazocine was 33.2 nM, showing that MR-2266 was 9.79-fold more effective than naloxone. These results suggest that eptazocine acted as a mu-receptor antagonist and as a kappa-receptor preferential agonist in isolated smooth muscle preparations.

P-489 - Preferential action of eptazocine, a novel analgesic, with opioid receptors in isolated guinea-pig ileum and mouse vas deferens preparations

Actions of eptazocine, a novel analgesic, on isolated smooth muscle preparations were investigated. Eptazocine (10(-5) M) slightly inhibited electrically-driven twitch-tension in guinea pig ileum preparations sensitive to mu- and kappa-agonists, and this effect was antagonized by 10(-7) M naloxone. Eptazocine (10(-5)-10(-4) M) inhibited such an effect by the mu-agonist morphine. In mouse vas deferens preparations having delta-, mu- and kappa-receptors, eptazocine (10(-7) M-) inhibited the twitch-tension in a dose-dependent manner, being hardly inhibited by naloxone. On the other hand, MR-2266 (10(-6) M), a relatively selective kappa-receptor antagonist, inhibited the eptazocine effect. The Ke (equilibrium dissociation constant) value of naloxone against eptazocine was 325 nM and the Ke value of MR-2266 against eptazocine was 33.2 nM, showing that MR-2266 was 9.79-fold more effective than naloxone. These results suggest that eptazocine acted as a mu-receptor antagonist and as a kappa-receptor preferential agonist in isolated smooth muscle preparations.

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

We have previously shown that μ 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 μ opioid receptors in the mouse vas deferens preparation differ from those in the guinea pig ileum, we investigated the possibility that the μ 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 pA 2 analyses were performed in the tolerant vasa deferentia (25 mg/kg) using naloxone, the pA 2 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 μ receptors, we conclude that the μ opioid receptors in the mouse vas deferens are not adequate models for those in the central nervous system to study the phenomenon of tolerance.

Lactamimides: A novel chemical class of calcium antagonists with diltiazem-like properties

The effects of a series of lactamimides on [ 3 H]d-cis- diltiazem binding to rat brain membranes, on [ 3H]nitrendipine binding to cardiac membranes, and on calcium-induced contractions in depolarized guinea pig taenia and ileum preparations were examined. Several of the lactamimides examined displaced [ 3 H]d-cis- diltiazem binding and antagonized, in a competitive fashion, calcium-induced contractions. Over the series of lactamimides, there was a highly significant, positive linear correlation ( r = 0.87, P < 0.001) between their potency to displace [ 3 H]d-cis- diltiazem and their potency to antagonize calcium-induced contractions in the depolarized taenia and ileum preparations. Of the lactamimides examined, MDL 16,582A [ N-(2,2-diphenylpentyl)azacyclotridecan-2-imine · hydrochloride] had potency equivalent to d- cis-diltiazem with p A 2 values of 7.27 and 7.38, respectively, against calcium-induced contractions in the guinea pig ileum. These lactamimides are a novel chemical class displaying diltiazem-like calcium antagonist properties.

Calcitonin gene-related peptide is metabolized by an endopeptidase hydrolyzing substance P

Calcitonin gene-related peptide (CGRP) is cleaved by an endopeptidase, also known to hydrolyze substance P (SP). The enzyme which was isolated from human cerebrospinal fluid, converted rCGRP into two products, clearly separable on HPLC. Amino acid analysis showed cleavage to occur at Leu 16-Ser 17. The carboxy-terminal fragment, rCGRP-(17–37), was weakly active in inhibiting 125I-rCGRP binding to a rat medulla oblongata membrane preparation, but it showed no binding to spinal cord membranes. The N-terminal fragment, rCGRP-(1–16), had very low or no affinity. Autoradiography with 125I-rCGRP showed distinct labelling of rat dorsal spinal cord, while there was no consistent pattern with 125I-rCGRP-(1–16). In the isolated guinea pig ileum preparation, the two fragments showed no CGRP-like activity. The ability of CGRP to interfere with SP degradation is offered as the explanation why CGRP has been reported to potentiate several biologic actions of SP.

Inhibition of gastrointestinal release of acetylchoune byquercetin as a possible mode of action of Psidium guajava leaf extracts in the treatment of acute diarrhoeal disease

The electrically stimulated guinea-pig ileum and spontaneously contracting guinea-pig ileum preparations were employed in studies on the effects of an alcoholic extract and two flavonoid compounds, quercetin and quercetin-3-arabinoside, extracted from the leaves of Psidium guajava. The extract showed a morphine-like inhibition of acetylcholine release in the coaxially stimulated ileum, together with an initial increase in muscular tone, followed by a gradual decrease. The morphine-like inhibition was found to be due to quercetin, starting at concentrations of 1.6 μg ml . The glycoside did not show any such action at concentrations of up to 1.28 mg ml . The extract inhibited spontaneous contractions in the unstimulated ileum with a concentration-response relationship.

An experimental study on dependence liability of zipeprol

Zipeprol, a piperazine ethanol derivative, is a non-essential but widely used (paediatric) antitussive, which is not legally considered as being capable of creating dependence or abuse liability. A first group of experimental results was obtained assaying the displacement of 1 n m [ 3H]naloxone by zipeprol vs morphine on the rat brain homogenate fractions. A second group was carried out on the longitudinal muscle of guinea-pig ileum, using the field stimulation technique, either in the absence or in the presence of naloxone 1 × 10 −5 m or in the absence or in the presence of yohimbine 1 × 10 −5 m. Further investigations concerning the pharmacological and the biochemical characterization of the mechanisms involved in abuse liability were carried out by means of the in vitro inhibition of ACh response on the guinea-pig ileum preparation. The results indicate zipeprol as a moderate opioid agonist, which also shows a direct anticholinergic effect, independent of presynaptic α 2 interaction.