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Home , Bremazocine, Ketazocine, Niravoline, Quadazocine

Bremazocine: A ê-Opioid Agonist with Potent Analgesic and Other Pharmacologic Properties

Juanita Dortch-Carnes1 and David E. Potter2

1Department of Pharmacology/Toxicology, Morehouse School of Medicine, Atlanta, GA, USA; 2Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, SC, USA

Keywords: Analgesia — Bremazocine — Diuresis — Dysphoria — ê-Opioid agonists — Ocu- lar hypotension — Respiration.

ABSTRACT

Bremazocine is a ê-opioid receptor agonist with potent analgesic and diuretic activities. As an analgesic it is three- to four-times more potent than morphine, as determined in both hot plate and tail flick tests. Bremazocine and other benzomorphan analogs were synthesized in an effort to produce opiates with greater ê-opioid receptor selectivity and with minimal morphine-like side effects. Unlike morphine bremazocine is devoid of physical and psychological dependence liability in animal models and produces little or no respiratory depression. While bremazocine does not produce the characteristic euphoria associated with morphine and its abuse, it has been shown to induce dysphoria, a property that limits its clinical usefulness. Similarly to morphine, repeated administration of bremazocine leads to tolerance to its analgesic effect. It has been demonstrated that the marked diuretic effect of bremazocine is mediated primarily by the central nervous system. Because of its psychotomimetic side effects (disturbance in the perception of space and time, abnormal visual experience, disturbance in body image perception, de-personaliza- tion, de-realization and loss of self control) bremazocine has limited potential as a clinical analgesic. However, its possible utility for the therapy of alcohol and drug addiction war- rants further consideration because of its ability to decrease ethanol and cocaine self-administration in non-human primates. In addition, the ability of bremazocine-like drugs to lower intraocular pressure and to minimize ischemic damage in animal models suggests their possible use in the therapy of glaucoma and cardiovascular disease.

Address correspondence and reprint requests to: Juanita Dortch-Carnes, Ph.D., Morehouse School of Med- icine, 720 Westview Dr. S.W., Atlanta, GA 30310-1495, USA. Tel.: +1 (404) 752-1755, Fax: +1 (404) 752-1164, E-mail: [email protected].

195 196 J. DORTCH-CARNES AND D. E. POTTER

Fig. 1. Absolute stereochemistry of bremazocine enantiomers.

OVERVIEW

Bremazocine is a benzomorphan analog that is commonly classified pharmacologically as a relatively selective ê-opioid receptor agonist. Although bremazocine functions as a potent analgesic when administered peripherally and centrally (87,88,99), it does not dem- onstrate cross-tolerance with morphine, produces minimal respiratory depression at analgesic doses, and substitutes for other ê-agonists in operant drug discriminatory procedures (87,106,117). As analgesics ê-opioid agonists appear to be more effective in females as compared to males. In some experimental settings, bremazocine has been shown to interact with other opioid receptors as well. For example, it possesses antagonist-like properties at the ì- and ä-receptors (30,88,117). Because of other pharmacologic actions, bremazocine or similar drugs might have clinical utility in diseases such as glaucoma, arthritis and inflammatory bowel syndrome.

DISCOVERY

Bremazocine, (2-[1-hydroxy-cyclopropylmethyl]-5-ethyl-9,9-dimethyl-2¢-hydroxy-6, 7-benzomorphan) is a member of the class of 9,9-dimethyl-6,7-benzomorphans, and was first synthesized at A. C. F. Chemiefarma and N. V. Maarssen in the Netherlands (99). It was synthesized in an effort to develop drugs that had greater receptor selectivity for ê-opioid receptors, because available evidence suggested that such agents would be powerful analgesics without morphine-like side effects. Efforts to optimize morphine-like compounds produced benzomorphan derivatives, ethylketocyclazocine (41,112) and bremazocine (99), both with relative selectivity for the ê-opioid receptor. The enantiomers of bremazocine (Fig. 1) have been found to have very different affinities at opioid receptors with different pharmacological activities and profiles (99). The opioid effects of racemic bremazocine have been found to be due largely to the agonist activity of its (–)-enantiomer at the ê-opioid receptor (99,21,14). The (–)-enantiomer of bremazocine is an important tool for opioid receptor studies; the (+)-enantiomer, which does not interact avidly with opioid receptors, has some of the non-opioid pharmacological effects of bremazocine.

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PHARMACOLOGY

Studies Characterizing the Analgesic Activity of Bremazocine Bremazocine, a potent, long-acting agonist that interacts with ê-opioid receptors, has been shown to be three- to four-times more potent than morphine in hot plate and tail flick tests in mice (99). Its analgesic activity in the tail flick test was antagonized more effec- tively by Mr-2266, a relatively selective ê-receptor antagonist, than by naloxone, a non- selective opioid receptor antagonist. Unlike morphine, bremazocine does not produce mydriasis or Straub tail phenomenon in mice. Moreover, it is devoid of respiratory depressant activity in rats. Initially, chronic administration of bremazocine to monkeys did not lead to a morphine-like withdrawal syndrome, although tolerance to its analgesic effects occurred; and in this paradigm, morphine remained an effective analgesic. Con- versely, treatment of morphine-tolerant animals with bremazocine did not cause analgesia. These data were interpreted as suggesting that ì-receptors are largely unoccupied by bremazocine and that ê-opioid receptors do not mediate analgesia. Subsequently, however, Spencer and coworkers demonstrated that bremazocine has analgesic activity in mice that is closer to that of pentazocine than to ethylketocyclazocine (114), using four antinociceptive tests. These results indicated that bremazocine may be active at ì- as well as ê-opioid receptors. The fact that abrupt cessation of administration of bremazocine precipitated a withdrawal syndrome in morphine-dependent rats supported this conclusion (115). As alluded to previously, in initial tests for analgesic activity, bremazocine was shown to be three- to four-times more potent than morphine (99). The two most common behavioral assays to assess such changes are the hot plate and tail flick tests, where a heat source is applied to either the hind paw or tail of an animal. Studies carried out in the late 1980s demonstrated the ability of bremazocine to produce an increase in the withdrawal response latency to noxious hind paw thermal stimulation in rats as early as two days after birth (50). In addition, bremazocine selectively inhibited the late C-fiber reflex discharge in cats, recorded in sectioned lumbo-sacral ventral root filaments, after supramaximal electrical stimulation of the ipsilateral sural or common peroneal nerve (5). Both effects were demonstrated to be dose-dependent and reversible by opioid antagonists. Further- more, in a study using nonhuman primates, bremazocine and other ê-agonists produced dose-dependent increases in tail-withdrawal latencies from both 50 and 55°C water (31). Studies examining bremazocine’s analgesic potential continued into the 1990s and its antinociceptive effects in rodents (6,52) and nonhuman primates (62,63) were again demonstrated to be dose-dependent and opioid receptor-mediated. After evaluating data related to the analgesic activity of bremazocine (Table 1), Romer and co-workers found that there were differences in the potency of the ê-opioid agonist when it was administered parenterally versus orally (99). When injected subcutaneously, bremazocine was determined to be three to four-times more potent than morphine as an analgesic agent. However, after oral administration to mice, bremazocine was only half as potent as morphine in the hot plate test, but three-times more potent in the tail flick pro- cedure. In the mouse, when compared to ketocyclazocine (a short-acting ê-opioid agonist), bremazocine was between three- and four-times less potent after subcutaneous administration, but approximately twice as potent by the oral route. When using the shock titration method (24) in the rhesus monkey (Table 2), bremazocine was found to be 180- and 57-times more potent than morphine or ketocyclazocine, respectively, when adminis-

CNS Drug Reviews, Vol. 11, No. 2, 2005 198 J. DORTCH-CARNES AND D. E. POTTER tered intravenously. In addition, bremazocine had a three-fold longer duration of action than ketocyclazocine. In another study, Furst compared the analgesic and sedative efficacy of ì- and ê-opioids as a function of time, in rats and mice (39). This study concluded that three opioid agonists with ê-receptor activity (bremazocine, ethylketocyclazocine, and pentazocine) were inactive against heat nociception, but like ì-agonists they produced potent, long-lasting analgesia in the acetic acid writhing test. In addition, when bremazocine was co-administered with morphine, there was a significant prolongation of the duration of analgesic action, without any influence on the potency. Furthermore, time-response curves and ED50 values of ê-opioid agonists were similar to those of ì-opioid agonists. The time-course of the analgesic effect of bremazocine in the mouse writhing test is compared to other ê-opioid agonists in Table 3. The adverse side effects of bremazocine include sedation, respiratory depression, diuresis and constipation. Hayes and Tyers examined the involvement of ì- and ê-opiate receptors in several opiate-like effects in conscious mice, which may correspond to clinical side effects (48). In this study, the authors tested a variety of opiate drugs with different selectivities for ì- and ê-opioid receptors for their effects on behavior, pupil di- ameter, body temperature, respiratory rate, and gastrointestinal propulsion. The investi- gators concluded that ì-receptor agonists produce their antinociceptive effects as well as opiate-like side effects by interacting with the ì-receptors. In regard to the ê-receptor agonists, such as bremazocine, the opiate-like side effects occurred at much higher doses than those needed for antinociception, suggesting that the ê-opioid agonist-induced side effects were due either to interaction with the ì-receptor or to some other non-specific action.

TABLE 1. Analgesic activity of bremazocine, ketocyclazocine and morphine, and their antagonism by naloxone, and Mr-2266 in mice

Test (n = 10, Parameter per dose) (mg/kg) Route Antagonist Bremazocine Ketocyclazocine Morphine d a b Hot plate ED50 s.c. None 0.7 0.17 2.1 p.o. 12d 20a 5.8c

Tail flick ED50 s.c. None 0.7 0.26 3.0 p.o. 7.5 18 20.5

Antagonism AD50 i.v. Naloxone >3.2 0.07 0.005 of analgesia (–44%) (tail flick) i.v. Mr-2266 0.46 0.043 0.008 a b c d Note. Optimal pretreatment times for the drugs were 15, 30, 60, 90 min; ED50, effective dose in 50% of the animals; AD50, antagonistic dose in 50% of the animals.

TABLE 2. Analgesic activity of bremazocine, ketocyclazocine, and morphine in rhesus monkeys Bremazocine Ketocyclazocine Morphine Test Parameter Route (n =5) (n =2) (n =4) Shock titration MED (mg/kg) i.v. 0.0056 0.32 1 Duration of action (min) 200 60 200 Note. MED, minimal effective dose. Data from ref. 99.

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Opioid Receptor Selectivity/Signal Transduction

The existence of multiple opioid receptor subtypes has been long recognized. These re- ä ê ì ceptors were initially termed , , and ; according to new nomenclature they are OP1, OP2, and OP3 receptors, respectively (71,75). More recently, the existence of opioid receptor subtypes has been confirmed by molecular cloning (17,35,122). ê-Opioid receptors are believed to arise first in evolution as indicated by nociception research in amphibians (110), followed by ä-opioid and ì-opioid receptors. Interestingly, the brain of amphibians expresses mostly ê-opioid receptor binding sites. Putative ê-opioid receptor subtypes are differentially labeled by arylacetamides (e.g., asimadoline) and benzomorphans (e.g., bre- ê ê mazocine): 1-receptors bind arylacetamides more avidly, whereas 2-receptors bind benzomorphans more selectively (100). The explanation for this differential binding, based upon structure-activity relationship, could be due to: 1) the putative existence of different affinity states (i.e., high affinity versus low affinity) of the same ê-opioid receptor; or 2) the existence of homo/heterodimer formation between various opioid receptors. For example, bremazocine has very similar affinity for the ê- and ì-opioid receptors but much less affinity for the ä-opioid receptor. Therefore, the non-selectivity and/or relative selectivity of bremazocine in a particular tissue could be based on either the existence of heterodimers consisting of ê-opioid receptor/ì-opioid receptor, or the preference for the low affinity state of the ê-opioid receptor homodimer. It should be noted that (–)-opioid receptor agonists can produce biological effects that are independent of opioid receptors particularly at higher doses. At low concentrations (nM), ê-opioid receptor agonists mediate spinal analgesia by actions on ê-opioid receptors, but at higher concentrations (ìM), cation (K/Ca) channel activity can be impaired independent of the activity at opioid receptors. With respect to spinal analgesia, there is evidence for gender-linked differences in the antinociceptive activity (46). For example, female rats show fluctuations in ê-opioid receptor density and sensitivity across the estrous cycle. Likewise, human females are ê reported to be more sensitive than males to the analgesic action of 2-opioid receptor agonists.

TABLE 3. Time course of the analgesic effect of ê-agonists in the mouse writhing test Percentage analgesia at time (min) Mean time (min) Dose, after drug administration* to reach 50% s.c. of maximal Compound (mg/kg) 10 20 30 60 90 120 analgesic effect Pentazocine 5.0 20 18 22 20 13 10 58 10.0 40 48 54 49 38 22 15.0 48 62 76 70 68 55 EKC 0.050 38 45 40 39 32 18 79 0.100 49 60 58 48 41 29 0.250 67 80 78 79 68 40 Bremazocine 0.05 66 NT 56 51 25 NT 64 0.10 88 NT 85 75 51 2 0.25 100 NT 100 88 75 23 *n/dose = 10 mice; EKC, ethylketocyclazocine; NT, not tested. Data from ref. 39.

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Studies conducted in the early to mid 1980s on isolated guinea pig ileum (77) and mouse vas deferens (46) indicated a preference of bremazocine for ê-opioid receptors. Binding studies with [3H](–)-bremazocine performed using rat brain membrane prepara- tions have shown that this compound differs in its binding properties from previously in- vestigated exogenous or endogenous opioids (99). In contrast to morphine, bremazocine did not produce mydriasis or the Straub tail phenomenon in mice. In addition, it lacks any significant effects on respiration in monkeys; likewise, programmed administration in the same species does not lead to a morphine-like withdrawal syndrome upon cessation of drug treatment or upon naloxone challenge. More recent studies utilizing the highly selective ê-opioid receptor antagonist, norbinaltorphimine (nor-BNI), confirmed that in many biological systems the effects of bremazocine are mediated primarily by ê-receptors (14,26,53,93,94,101). James and Goldstein developed a method for measuring binding selectivity of ligands for multiple opioid receptors. By using radioligands, that were partially selective for each receptor type, in combination with brain membranes enriched in a particular receptor type, they found that the selectivity profile for bremazocine was 3.1, 19, and 10.1 for ì, ä, and ê receptors, respectively (59). Because the anatomical distribution of ê-opioid receptors in the central nervous system across species has shown widespread and significant differences, it is important to con- sider the ê-opioid receptor distribution in humans. As shown by RT-PCR, expression of ê-opioid receptor mRNA in the human brain is consistent with the involvement of ê-opioid receptors in pain perception, neuroendocrine physiology, and affective behavior and cognition (107). In general, the distribution of ê-opioid receptors follows the pattern of prodynorphin-derived peptides. The cloned ê-opioid receptor has high affinity for dynorphin-A (1-17), an endogenous ê-opioid agonist (16), and for the synthetic ê-selective ligands U-50488H and U-69593, confirming that the cloned receptor is of the ê-opioid receptor type. Pharmacological studies with ê-selective ligands demonstrated the existence of two distinct subtypes of ê ê -opioid receptors, one of which is U-69593-sensitive ( 1) and the other bremazocine-sen- ê ê ê ê sitive ( 2). Both subtypes of the -opioid receptors ( 1 and 2) have been further divided into four types (19,86,127). The absence of subdivision-specific antagonists limits the studies of pharmacological properties of these putative subdivision-selective agonists. It ê has been shown that the application of a 1-selective, irreversible antagonist inhibited the ê antinociceptive effect of U-69593 (a 1-selective agonist) without inhibiting the agonist ê property of bremazocine (a 2-selective agonist), suggesting the existence of subdivisions ê ê within the 1- and 2-subtypes (113). However, it is possible that the subdivisions within the respective subtypes could represent either different affinity states of a (–)-opioid receptor subtype, or homo/heterodimers. Although widely used as a ê-opioid agonist, bremazocine has been reported to have roughly equal affinities at the ì-, ä-, and ê-binding sites (72). Bremazocine, as well as other ê-opioid receptor agonists, have been demonstrated to have moderate affinity for the ó ó 1-receptor subtype. The -receptor was initially classified as an opioid receptor (45). However, since the time it was cloned in 1996 (75), it has become evident that the ó-receptor is a single transmembrane-spanning protein targeted by other drugs of abuse and is no longer considered to be a member of the opioid receptor family. At the cellular level, it has been demonstrated that, ê-opioid receptors are predominant- / ly coupled to heterotrimeric Gi Go proteins that are sensitive to pertussis toxin (PTX). In

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ê / some cells, the coupling of -opioid receptors to PTX-insensitive Gs Gz proteins has been described. In the native state, activation of the ê-opioid receptors usually evokes stimulation of phospholipase-Câ-induced inhibition of adenylyl cyclase, inhibition of vesicular release of neurotransmitters and interactions with a number of cation channels, including K+-channels (G-protein inwardly rectifying, delayed rectifying, and Big-K) and voltage- sensitive Ca2+ channels. In most excitable tissues, K-channel activities are stimulated whereas calcium channel activity is inhibited. The activities of the described effectors are modulated by both the GTP-bound form of the Gs-subunit as well as free Gâã-subunits. The Gi-mediated events are modulated by RGS proteins that reduce the lifetime of Gâã-GTP thereby terminating its effects. Liberated Gâã subunit is presumed to activate specific isoforms of phosphatidyl inositol 3-kinase; subsequently, this event leads to activation of Ras and the Raf/MEK/Erk kinase cascade promoting protective and/or anti- apoptotic effects (111). Bremazocine has been shown to be a pure antagonist at the ä-receptor in the hamster vas deferens (76), and at the ì-receptor in the rat vas deferens (42). It has now been accepted that the cellular activities of ê-opioid receptors are modulated dy- namically by dimerization and by desensitization/downregulation. In contrast to ì-opioid receptors and ä-opioid receptors, ê-opioid receptors do not seem to be predisposed to endocytosis. Studies conducted in our laboratory using the isolated iris-ciliary body preparation from New Zealand White rabbits have demonstrated a biphasic or bimodal effect of bremazocine on cAMP accumulation (101). A a concentration of 0.0001 ìM bremazocine enhanced isoproterenol (ISO)-stimulated cAMP accumulation, whereas at concentrations of 0.01 to 10 ìM, bremazocine was inhibitory. However, in the absence of stimulation by ISO, bremazocine at the same concentrations elevated cAMP levels above base levels. These effects were antagonized by pretreatment with nor-BNI suggesting that (–)-opioid receptors were involved. Inhibitory effects on cAMP accumulation could be antagonized by pretreatment with PTX indicating the involvement of a Gi protein. The biphasic nature of cAMP in this tissue could reflect differences in the activation (or inhibition) of isoforms of either adenylyl cyclase (formation) or phophodiesterase (degradation).

Effects on Motor Activity In rodents, ì- and ä-agonists usually increase locomotion, whereas ê-agonists decrease locomotion (73) in addition to inducing ataxia and sedation (57). However, in preweanling (29) and monoamine-depleted rats (54), ê-opioid agonists have been reported to markedly increase locomotor activity. In Syrian hamsters, ê-agonists elicit biphasic effects inducing hyperactivity at lower doses and hypoactivity at higher doses (105). In a study comparing the ability of the ê-opioid agonists U-50488H, BRL-52537, and bremazocine to modify spontaneous motor activity in mice (66), it was determined that higher analgesic doses of each of the ê-agonists reduced rearing, motility, and locomotion in non-habituated animals. These effects were blocked by the selective ê-opioid receptor antagonist, nor-BNI, and the irreversible, relatively selective ê-receptor antagonist, DIPPA. In contrast, lower sub-analgesic doses of bremazocine (0.075 mg/kg) time-dependently increased motor activity that were not blocked by nor-BNI or DIPPA, but were completely eliminated by naloxone (0.1 mg/kg), thus indicating that the stimulatory effects of the ê-opioids on locomotor activity were mediated, in part, by opiate receptors other than the ê-subtypes. The stimulatory effects of U-50488H and bremazocine were not observed in habituated animals.

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Effects on Ethanol and Cocaine Use

Endogenous opioid peptides have been suggested to be involved in ethanol and cocaine addiction (51,83). In regard to the effects of bremazocine on alcohol and drug use, Nestby and colleagues reported that bremazocine displayed a mixed-action at multiple types of opioid receptors in rat brain (83). In addition, bremazocine caused a prolonged inhibition of 24 h free-choice ethanol self-administration without affecting natural reinforcement and without rapid development of tolerance to its inhibitory effect. In a separate study conducted by Cosgrove and Carrol, pretreatment with bremazocine dose-dependently de- creased self-administration of cocaine, ethanol and phenylcyclohexylpiperidine (PCP) (22). This effect was generalized to non-drug reinforcers (saccharin and food) indicating that bremazocine did not selectively decrease drug-maintained behavior. Bremazocine treatment was also effective in reducing the demand and response strength of smoked cocaine (base), oral ethanol and PCP. Mello and Negus found that bremazocine and two other ê-agonists reduced cocaine self-administration in rhesus monkeys. This suppression of self-administration of cocaine was maintained over 10 days of drug treatment (78).

Discriminative Stimulus Effects

The discriminative stimulus property of bremazocine was first demonstrated in the rat (106). This characteristic was determined to be a result of an interaction of bremazocine with ê-opioid receptors and ó-receptors; the latter receptors were formerly considered part of the opioid receptor family (75), but are now considered to constitute a distinct group of receptors (97). Studies in pigeons (91), squirrel monkeys (82,94), and rats (92) produced further evidence of the discriminative stimulus properties of bremazocine and other ê-opioids (13). More recent studies have demonstrated that the discriminative stimulus effect of the ê-opioid receptor agonist, enadoline, could be reproduced by bremazocine and other ê-agonists (15).

Effects on Anterior Pituitary Hormones

ê-Opioid receptor agonists are known to cause demonstrable neuroendocrine effects in humans and nonhuman primates that include release of the anterior pituitary peptide hormones, such as prolactin (40,89,116). As early as 1976, it has been demonstrated that morphine and other opioid compounds such as the then new benzomorphan derivative, bremazocine, inhibit the secretion of luteinizing hormone (LH) in rats of both sexes (12,18,85). Marko and Romer found that acute administration of bremazocine (0.005–1 mg/kg, s.c.) or morphine (10–20 mg/kg, s.c.) diminished serum LH levels and spontaneous ovulation in female rats in a dose-dependent manner (74). Chronic treatment with bremazocine significantly diminished LH and testosterone secretion in male rats, which in turn led to a reduced weight of the prostate gland, while prolactin and follicle stimulating hormone (FSH) secretions were not significantly affected. Pretreatment with the ì-receptor antagonist, naloxone, which increases LH secretion in rats, significantly antagonized the inhibiting effect of morphine, but not that of bremazocine on LH secretion. It was, therefore, concluded that morphine and bremazocine showed qualitative and quanti- tative differences in their endocrine activity profiles.

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Diuretic Effect

ê-Opioid agonists are unique among opioid-receptor agonists in that they consistently produce diuresis over a relatively wide dose-range (68,69); other opioids, such as morphine, can produce both antidiuretic and diuretic effects depending on the dose and species used (4). Synthetic benzomorphans such as ethylketocyclazocine, ketazocine, and bremazocine, have been found to increase urine output in normally hydrated as well as in water-loaded animals (55,68,69,98,103,109). Several studies in rodents have reported that the ê-opioid receptor-mediated diuretic effect is due mainly to inhibition of vasopressin release from the neurohypophysis (69,84,121). Studies in primates also suggest the involvement of vasopressin (ADH) in the diuretic effects of ê-agonists (7,64) as well as the presence of ê-opioid receptors in relevant hypothalamic nuclei (90,108). Although one study has shown that the diuretic effect of bremazocine is mediated partially in the periphery (103), most studies indicate that the diuretic effect of ê-agonists is mediated primarily in the central nervous system (11,60,68).

Cardiovascular Effects

The action of opioids on the cardiovascular system varies according to dose, species examined, and route of administration (33,104). Some studies have demonstrated a morphine-mediated cardiovascular effects linked to the central nervous system (37,67). How- ever, in intact animals, bremazocine activates ê-opioid receptors centrally and peripherally to produce dose-dependent hypotension and bradycardia. These effects are attributable to inhibition of sympathoadrenal outflow as demonstrated by reductions in plasma levels of norepinephrine (34). El-Sharkawy and colleagues performed in vitro experiments that generated evidence of the direct effects of bremazocine (32) and other opioid agonists (9) on vascular smooth muscle. The effects of the agents varied depending on the agonist used, the concentration tested, and the pre-contracting agent used. In aortic rings pre-contracted with norepinephrine, U-50488H, ethylketocyclazocine (EKC), and morphine caused constriction at low concentrations, but relaxation at high concentrations; bremazocine caused only relaxation over a relatively wide dose range. Bremazocine did, however, produce contraction in tissues pre-contracted with prostaglandin F2á. Dependence on the pre-contracting agent may have its basis in the difference between the mechanisms by which various pre-contracting agents evoke increases in vascular smooth muscle tone. In studies on pithed rabbits with continuously stimulated sympathetic outflow, EKC (33) and bremazocine (34) were shown to persistently decrease the release of norepinephrine and, consequently, lower blood pressure. In separate studies, bremazocine (0.2 mg/kg, i.v.) produced a slight decrease in systolic blood pressure only at 45 min after drug administration (P < 0.02); no change in diastolic or mean blood pressure was observed at this time point. A marked decrease in blood pressure was observed with 0.4 mg/kg, i.v. bremazocine; the peak effect was observed at 60 min after drug administration (P < 0.0005). The change occurred in both systolic and diastolic blood pressures. Higher doses (0.6 mg/kg, i.v.) of bremazocine did not produce any additional change in systolic, diastolic or mean blood pressures. A significant dose-dependent decrease in heart rate was produced by bremazocine (0.2–0.6 mg/kg, i.v.). The bradycardia was most marked at 60 min after drug administration.

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In the heart, ischemic preconditioning (IPC) is a phenomenon of increased resistance to cellular injury or prolonged ischemia that follows exposure to single or multiple periods of brief coronary occlusion. The phenomenon has two phases: an acute or early phase that lasts for about 1–3 h, and a delayed phase that appears approximately 24 h after the acute phase. The delayed phase may last for up to 72 h. Opioid receptor activation, specifically ä and ê, seems to be an important component of both the acute and delayed phases of IPC. Bremazocine has been reported to exacerbate infarct size in the isolated rat heart through an as yet unknown mechanism (1). In contrast, prior stimulation of ê-opioid receptors with the selective agonist, U-50488H, reduced lactate dehydrogenase (LDH) activity (an index of cell injury) and increased the percentage of non-blue cells (an index of viability) in the culture medium of rat ventricular myocytes (126). The induction of heat shock protein (HSP-70) appears to mediate the delayed cardioprotection induced by pretreatment with U-50448H. Both the “anti-preconditioned state” (bremazocine) and the delayed cardioprotection (U-50448H) were antagonized by the relatively selective antagonist, nor-BNI. These seemingly paradoxical findings could reflect the biphasic effect bremazocine has on signal transduction pathways such as adenylyl cyclase/cAMP. In other cases, ê-receptor agonists, particularly those in the arylacetamide class, blocked Na/K channels in the heart that are independent of action on “classical” opioid receptors (96). These receptor-independent effects could account for the activity of ê-receptor agonists in models of ischemia and/or arrhythmias.

Respiratory Effects Respiratory depression is a clinically significant effect of many opioid analgesics. The respiratory depressant effects of opioids are dose-related, stereospecific and reversed by opioid antagonists (59), indicating that the respiratory effects are mediated through opioid receptors. ì-Selective agonists such as morphine, induce pronounced effects on respiration at analgesic doses (61). In contrast, ê-selective opioids, like bremazocine (38,99), produce only modest suppressive effects on respiration at doses that produce analgesia in dogs (38) and rodents (48,99). Studies with primates generated slightly different results (14) in that bremazocine and other ê-agonists were found to produce significant respiratory depression at high doses. In the same study, the most selective ê-agonist studied, U-50488H, had only modest effects on respiration at all doses; thereby, suggesting that the respiratory effects of the opioids used were not mediated through a ê-receptor mechanism. Hayes and Tyers found that the analgesia produced by Mr-2034 and bremazocine was mediated through ê-receptors. It was concluded that the opioid side effects that appeared at much higher doses, including respiratory depression induced by bremazocine, could be at- tributed to an interaction with the ì-receptor or to some other nonspecific action (48). In any event, the studies in non-human primates reinforce the suggestion that the respiratory depressant effects of bremazocine and other more non-selective ê-agonists occur at much higher doses than those required to induce analgesia and behavioral changes.

Effects on Neurotransmission Although a few reports have been generated concerning the effects of ê-opioid agonists on biogenic amine-derived neurotransmitters such as norepinephrine, acetylcholine and the amino acid neurotransmitters (aspartate, glutamate, and ã-aminobutyric acid), for the most part the effects of ê-agonists on neurotransmission in the central nervous system are

CNS Drug Reviews, Vol. 11, No. 2, 2005 BREMAZOCINE 205 largely associated with dopamine. It is well documented that dopaminergic activity can be modulated by more than one type of opioid receptors. In general, it is agreed that ì-selective agonists increase, whereas ê-selective agonists decrease dopamine release in the brain (23). In keeping with this premise, bremazocine has been demonstrated to inhibit the release of dopamine in the nucleus accumbens and in the dorsal caudate of freely moving rats (23). This effect was shown to be mediated by activation of ê-opioid receptors. Bremazocine’s effect on norepinephrine and amino acid neurotransmitter release has been shown to be inhibitory and also linked to activation of ê-receptors. Heijna and colleagues have generated evidence that the inhibitory effect of bremazocine on dopamine activity is linked to activation of ä-opioid receptors coupled to DA-sensitive adenylate cyclase (49). The finding that ì- and ê-agonists produce opposite effects on dopamine release would predict that ì- and ê-agonists might have also opposite effects on the reinforcing properties of cocaine. However, if ê-agonists like bremazocine, EKC, Mr-2033 and enadoline act as low efficacy ligands for ì-receptors, the combination of low efficacy ì- and high efficacy ê-activity could result in complementary effects on cocaine self-administration. Archer and colleagues have suggested that the combination of a short-acting ê-agonist and a long-acting ì-antagonist could be especially useful for cocaine abuse treatment, because both ê-agonists and ì-antagonists reduce dopamine release from the nucleus accumbens (3). Because ê-opioid agonists, such as bremazocine, have been shown to inhibit veratri- dine-induced calcium influx and glutamate release in mammalian cerebral cortical slices (10), one would predict that activation of ê-opioid receptors should offer some level of neuroprotection. Indeed, Chen and colleagues demonstrated that pretreatment with BRL-52537 provided robust neuroprotection in rats without altering ischemia-evoked release of dopamine and its metabolites (17). Perhaps this property could be utilized to treat other neuropathies, including the optic neuropathy that characterizes glaucoma.

Ocular Effects

Evidence of the presence of opioid receptors in the iris of rabbits and humans was first generated in the 1980s (27,28,36). In addition, the intraocular pressure lowering effect of morphine has been demonstrated in both animal and human subjects (28). Similar to morphine, bremazocine has been demonstrated to lower the intraocular pressure in rabbits (102). Further studies with bremazocine have generated information regarding the mechanism of this effect. Bremazocine-induced ocular hypotension has been linked to activation of ê-opioid receptors, because the response was inhibited by pretreatment with nor- BNI, a relatively selective ê-receptor antagonist (102). Furthermore, the intraocular pressure lowering effect of bremazocine was demonstrated to be associated with inhibition of cAMP and norepinephrine release in the iris-ciliary body (ICB) of rabbits (101), as well as increases in atrial natriuretic peptide (93,101) and inositol phosphate levels in the rabbit ICB preparation (26). More recently, bremazocine has been shown to elevate CNP levels in the aqueous humor of rabbits, and this event was associated with an increase in total outflow facility (93). Because the increase in outflow facility could be antagonized by pretreatment with either isatin (a purported NPR antagonist) or nor-BNI (a relatively selective ê-opioid receptor antagonist), an association was made between the ability of bremazocine to elevate CNP/ANP levels and increase outflow facility. Thus, it was concluded that the enhanced

CNS Drug Reviews, Vol. 11, No. 2, 2005 206 J. DORTCH-CARNES AND D. E. POTTER egress of aqueous humor caused by bremazocine is mediated, in part, by a paracrine effect of natriuretic peptides on outflow pathways.

Clinical Relevance

ê-Opioid agonists are of particular clinical interest as analgesics because of their ability to modulate antinociceptive functions without ì-opioid-related side-effects including constipation, pruritus, and respiratory depression. However, the centrally-mediated effects of ê-agonists, such as sedation and dysphoria, tend to limit their potential clinical usefulness (89,119). It is possible that ê-agonists that do not penetrate the pial-glial barrier would have greater utility. Although no clinical trials have been conducted with bremazocine in humans, a number of clinically relevant experiments using various animal models have been performed. Initially, the majority of these type studies were centered on the possible use of bremazocine as an opioid analgesic that would be devoid of the bothersome side effects associated with the use of morphine. Indeed, bremazocine has been demonstrated to be a potent long-lasting analgesic in rodents and nonhuman primates. Clinical studies have indicated that sensitivity to analgesia induced by ê-opioid agonists is influenced to a significant degree by gender (females > males). More recent studies with bremazocine in sub- human primates indicate the possibility of treating substance abuse (e.g., cocaine).

Adverse Effects, Tolerance, and Dependence

A number of clinical studies have revealed that members of the benzomorphan class of ê-opioids elicit psychotomimetic and dysphoric effects similar to those of the dissociative anesthetics [e.g., phencyclidine (PCP) and ketamine]. Initial pharmacologic studies suggested that these effects of the ê-agonists were mediated by ó-(PCP) receptors (75,128). Later, it was determined that they were mediated principally by activation of ê-opioid receptors (65,89). Because humans are the only species in which psychotomimetic parameters can be measured, a pertinent question that remains to be answered is: What are the human equiv- alents of the ê-opioid receptor-induced aversive effects in rodents and monkeys? Detailed clinical studies of the effects of the benzomorphan derivatives cyclazocine (44), N-allyl- normetazocine (25), and Mr-2033 (56,79,80), determined that these compounds induced some or all of the psychotomimetic effects mentioned above. Unlike morphine, bremazocine (32 mg/kg, s.c.) has not produced mydriasis or the Straub tail phenomenon in mice, nor has it induced respiratory depression in rats (99). Bremazocine’s adverse effects and development of tolerance have been examined most extensively in pre-clinical studies using monkeys. However, as with morphine, repeated administration of bremazocine has led to the development of tolerance to its analgesic effect. Mello and Negus demonstrated evidence of transient sedation and occasional vom- iting produced by bremazocine in in a preclinical chronic study including monkeys (78). In a separate study of monkeys that were programmed to self-administer bremazocine, neither naloxone challenge nor cessation of drug treatment led to morphine-like withdrawal symptoms (99). Only yawning, head shaking, and some retching were observed. In a self-administration human study, despite continual access to the drug for a total of six weeks, bremazocine was not self-administered, thus suggesting that it may have consid-

CNS Drug Reviews, Vol. 11, No. 2, 2005 BREMAZOCINE 207 erably less abuse potential than morphine in humans as well (99). However, bremazocine has very limited potential as a therapeutically useful analgesic due to its psychotomimetic side-effects.

CONCLUSIONS

ê-Opioid receptor agonists have become important pharmacological tools in studying a variety of functions modulated by opioid receptors (2,125). Preclinical studies suggest the possibility of their utility in specific therapeutic areas. For example, they are being eval- uated in the treatment of cocaine abuse (20,81) due to their ability to lower excessively elevated dopamine levels in the nucleus accumbens. More recently, ê-agonists have been considered for their potential usefulness in the therapy of HIV-1 (70) and ischemia-related cardiovascular disorders (95). Future preclinical studies examining the potential usefulness of bremazocine and other ê-opioid agonists as potential therapy for the above mentioned chronic disease states will have to ultimately address the issues of tolerance, duration of action, and severity of unde- sirable side effects such as emesis, sedation and dysphoria. Alternatively, centrally-mediated side effects can be minimized by site-directed delivery or new formulations. The use of combinations of low efficacy ì- and high efficacy ê-agonists, as was suggested for therapy of cocaine addiction, should also be considered. Another potential therapeutic in- dication for peripherally acting ê-opioid receptor agonists (e.g., asimadoline) is arthritis (8,118). ê-Opioid receptor agonists act at multiple sites in the inflammatory cascade to: 1) reduce adhesion molecule expression; 2) inhibit cell trafficking; 3) suppress mRNA expression and protein levels of substance-P and calcitonin gene-related protein; and 4) reduce TNF-(expression and release). The ability of ê-opioid receptor agonists to suppress TNF-(expression) could also have some potential benefit in treating glaucomatous neurodegeneration (120,123). Currently, further research with bremazocine is limited by the availability of the compound. However, one group has developed a novel method of synthesizing the ê-opioid enantiomers (43), thereby facilitating their availability for continued use as pharmacological tools for the in vitro and in vivo exploration of the ê-opioid receptor system. Additional preclinical research with ê (–)-opioid agonists, such as bremazocine, is needed to determine their potential utility in the treatment of: 1) drug/alcohol dependence; 2) gastrointestinal disorders, such as irritable bowel syndrome; 3) cardiovascular diseases; 4) arthritis; and 5) glaucoma. Acknowledgments. The research on bremazocine’s ocular effects was supported by NIH/NEI grants EY-011977, EY-012807 and EY-014793. The authors express their sincere appreciation to Luanna Bartholomew for her assistance in preparing this review.

ADDENDUM. Chemical Names of Compounds ANP, atrial natriuretic peptide; BRL-52537,(+/–)-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperadine; CNP, C–type natriuretic peptide; DIPPA, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)-

CNS Drug Reviews, Vol. 11, No. 2, 2005 208 J. DORTCH-CARNES AND D. E. POTTER ethyl]acetamide; EKC, ethylketocyclazocine; HSP-70, heat shock protein 70; Mr-2266, (–)-(1R,5R,9R)-5,9-diethyl-2-(3–furylmethyl)-2¢-hydroxy-6,7-benzomorphan; Mr-2033,(+/–)-(1-R/S,5-R/S,2=R/S)-5,9-dimethyl-2¢-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan; Mr-2034, (–)-N-(2-tetrahydrofurfuryl)-normetazocine; Nor-BNI, nor–binaltorphimine; U-50488H, 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzene-acetamide; U-69593, trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)cyclohexyl]benzene-acetamide methanesulfonate.

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