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Life Sciences 1990An increasing amount of evidence suggests the existence of specific binding sites for psychotomimetic drugs from the opiate-benzomorphan and arylcyclohexylamine series.... (Review)
Review
An increasing amount of evidence suggests the existence of specific binding sites for psychotomimetic drugs from the opiate-benzomorphan and arylcyclohexylamine series. The sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine and (+)pentazocine and also for some neuroleptics (e.g., haloperidol). The PCP receptor has preferential affinity for phencyclidine (PCP) analogs and other non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists. The physiological significance of the PCP receptor is associated with the blockade of the NMDA type of the glutamate receptor, implying a neuroprotective role of the PCP receptor. However, the significance of the sigma binding sites is less conspicuous. It is not only that drugs from distinct pharmacological classes display a certain degree of affinity for the "sigma/haloperidol" binding sites, but also that drugs which do not induce or block psychotomimetic activity, i.e., (+)3-(3-hydroxyphenyl)-N-(1-propyl) piperidine [(+)3-PPP] and 1,3-di-o-tolyl-guanidine (DTG), display relatively high affinity for the sigma binding sites. The diversity of the compounds which are proposed to interact with the sigma receptors and the variety of the responses elicited by these drugs suggest the existence of sigma receptor subtypes. The finding that the type A of monoamine oxidase (MAO) inhibitors, which are used in treatment of affective disorders, display high affinity for the sigma binding sites suggests their involvement in affective or schizoaffective disorders. Revealing the existence of sigma receptor subtypes may help to elucidate their association with various psychiatric disorders.
Topics: Animals; Benzomorphans; Brain; Cyclohexylamines; Humans; Mental Disorders; Monoamine Oxidase Inhibitors; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma
PubMed: 2172677
DOI: 10.1016/0024-3205(90)90165-n -
Molecules (Basel, Switzerland) Jun 2023In this work, we report on the in vitro and in vivo pharmacological properties of LP1 analogs to complete the series of structural modifications aimed to generate...
In this work, we report on the in vitro and in vivo pharmacological properties of LP1 analogs to complete the series of structural modifications aimed to generate compounds with improved analgesia. To do that, the phenyl ring in the -substituent of our lead compound LP1 was replaced by an electron-rich or electron-deficient ring and linked through a propanamide or butyramide spacer at the basic nitrogen of the (-)---normetazocine skeleton. In radioligand binding assays, compounds and were found to display nanomolar binding affinity for the μ opioid receptor (MOR) (K = 5.96 ± 0.08 nM and 1.49 ± 0.24 nM, respectively). In the mouse vas deferens (MVD) assay, compound showed an antagonist effect against DAMGO ([D-Ala, N-MePhe, Gly-ol]-enkephalin), a highly selective MOR prototype agonist, whereas compound produced naloxone reversible effect at MOR. Moreover, compound , as potent as LP1 and DAMGO at MOR, was able to reduce thermal and inflammatory pain assessed by the mouse tail-flick test and rat paw pressure thresholds (PPTs) measured by a Randall-Selitto test.
Topics: Male; Rats; Mice; Animals; Analgesics, Opioid; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Ligands; Receptors, Opioid, mu; Cyclazocine; Pain
PubMed: 37375382
DOI: 10.3390/molecules28124827 -
The American Journal on Addictions 2009There is increasing evidence that the kappa-opiate receptor, in addition to the mu-opiate receptor, plays an important role in substance use pathophysiology and... (Review)
Review
There is increasing evidence that the kappa-opiate receptor, in addition to the mu-opiate receptor, plays an important role in substance use pathophysiology and behavior. As dopamine activity is upregulated through chronic substance use, kappa receptor activity, mediated through the peptide dynorphin, is upregulated in parallel. Dynorphin causes dysphoria and decreased locomotion, and the upregulation of its activity on the kappa receptor likely dampens the excitation caused by increased dopaminergic activity. This feedback mechanism may have significant clinical implications for treating drug dependent patients in various stages of their pathology.
Topics: Brain; Ethylketocyclazocine; Humans; Locomotion; Morphinans; Receptors, Opioid, kappa; Spiro Compounds; Substance-Related Disorders; Up-Regulation
PubMed: 19444730
DOI: 10.1080/10550490902925862 -
Frontiers in Psychiatry 2021Opioids and stimulants are often used in combination for both recreational and non-recreational purposes. High-efficacy mu opioid agonists generally increase the...
Opioids and stimulants are often used in combination for both recreational and non-recreational purposes. High-efficacy mu opioid agonists generally increase the behavioral effects of stimulants, whereas opioid receptor antagonists generally attenuate the behavioral effects of stimulants; however, less is known regarding the interactions between stimulants and opioids possessing low to intermediate efficacy at the mu receptor. The purpose of this study was to examine the role of an opioid's relative efficacy at the mu receptor in altering the behavioral effects of dextro(-)amphetamine. To this end, opioids possessing a range of relative efficacy at the mu receptor were examined alone and in combination with cumulative doses of -amphetamine on a test of open-field, locomotor activity in male rats. Levorphanol, buprenorphine, butorphanol, nalbuphine, (-)-pentazocine, (-)-metazocine, (-)-cyclazocine, (-)-NANM, and nalorphine increased the locomotor effects of -amphetamine in either an additive or greater-than-additive manner according to an effect-additive model. Only the selective, high-efficacy kappa agonist, spiradoline, and the non-selective opioid receptor antagonist, naloxone, failed to increase the effects of -amphetamine under the conditions examined. These data indicate that opioids possessing a large range of relative efficacy at the mu receptor, including those possessing very low relative efficacy, significantly increase the locomotor effects of -amphetamine.
PubMed: 35069292
DOI: 10.3389/fpsyt.2021.790471 -
Molecules (Basel, Switzerland) Aug 2022Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The...
Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (σR) antagonism, could be an opioid adjuvant strategy. The in vitro σR and σR profiles of previous synthesized MOR/DOR agonists (-)-2/-LP2 (), (-)-2-LP2 (), and (-)-2-LP2 () were assayed. To investigate the pivotal role of -normetazocine stereochemistry, we also synthesized the (+)-2/-LP2 (), (+)-2-LP2 (), and (+)-2-LP2 () compounds. (-)-2/-LP2 (), (-)-2-LP2 (), and (-)-2-LP2 () compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2/-LP2 (), (+)-2-LP2 (), and (+)-2-LP2 () isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (-)-2-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2/-LP2 (), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed -normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.
Topics: Analgesics; Analgesics, Opioid; Cyclazocine; Humans; Narcotic Antagonists; Pain; Receptors, Opioid, mu; Receptors, sigma; Sigma-1 Receptor
PubMed: 36014375
DOI: 10.3390/molecules27165135 -
Bulletin of the World Health... 1969This report-the second of a series on codeine and its alternates for pain and cough relief-contains a detailed evaluation of experimental and clinical data on newer... (Review)
Review
This report-the second of a series on codeine and its alternates for pain and cough relief-contains a detailed evaluation of experimental and clinical data on newer substances having analgesic properties comparable to and in approximately the same range as those of codeine. The data are discussed under the headings: analgesic effects in animals; clinical usefulness; side-effects with particular reference to dependence and abuse liability.
Topics: Amides; Analgesics; Animals; Antitussive Agents; Azepines; Carisoprodol; Cats; Chickens; Codeine; Cough; Cyclazocine; Dextropropoxyphene; Diphenylacetic Acids; Dogs; Ducks; Guinea Pigs; Humans; Indenes; Indoles; Isoquinolines; Mice; Morphinans; Nalorphine; Narcotic Antagonists; Pain; Pentazocine; Phenethylamines; Pyrrolidines; Rats; Substance-Related Disorders; Thalidomide
PubMed: 4894737
DOI: No ID Found -
Psychopharmacology 1984dl-Ethylketazocine (EKC, 0.01 mg/kg) and saline were established as discriminative stimuli for food-maintained responding in macaque monkeys. Thirty consecutive presses...
dl-Ethylketazocine (EKC, 0.01 mg/kg) and saline were established as discriminative stimuli for food-maintained responding in macaque monkeys. Thirty consecutive presses on a right or left lever were reinforced with food, contingent on whether EKC or saline were administered before the session. For tests of antagonism, naltrexone, or UM 979 [(l)-5,9-alpha-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan] was administered concomitantly with EKC, dl-cyclazocine, or nalorphine. Both antagonists blocked completely the EKC discriminative stimulus. The antagonism of the stimulus and rate-altering effects of EKC was surmountable, with considerable intersubject variability in the magnitude of the EKC dose increase required to overcome the blockade. Cyclazocine and nalorphine, mixed agonist-antagonist opioids that share stimulus properties with EKC, were also susceptible to antagonism. Naltrexone antagonized completely the EKC stimulus effects of nalorphine; naltrexone and UM 979 antagonized completely the EKC stimulus effects of cyclazocine. Naltrexone antagonism of the cyclazocine stimulus was not surmountable, due to a lack of antagonism of the rate-decreasing effects of high cyclazocine doses.
Topics: Analgesics, Opioid; Animals; Cyclazocine; Discrimination, Psychological; Ethylketocyclazocine; Macaca mulatta; Macaca nemestrina; Male; Nalorphine; Naltrexone; Narcotic Antagonists
PubMed: 6151208
DOI: 10.1007/BF00555213 -
Proceedings of the National Academy of... Jun 1988kappa opioid receptors (kappa receptors) have been characterized in homogenates of guinea pig and rat brain under in vitro binding conditions. kappa receptors were...
kappa opioid receptors (kappa receptors) have been characterized in homogenates of guinea pig and rat brain under in vitro binding conditions. kappa receptors were labeled by using the tritiated prototypic kappa opioid ethylketocyclazocine under conditions in which mu and delta opioid binding was suppressed. In the case of guinea pig brain membranes, a single population of high-affinity kappa opioid receptor sites (kappa sites; Kd = 0.66 nM, Bmax = 80 fmol/mg of protein) was observed. In contrast, in the case of rat brain, two populations of kappa sites were observed--high-affinity sites at low density (Kd = 1.0 nM, Bmax = 16 fmol/mg of protein) and low-affinity sites at high density (Kd = 13 nM, Bmax = 111 fmol/mg of protein). To test the hypothesis that the high- and low-affinity kappa sites represent two distinct kappa receptor subtypes, a series of opioids were tested for their abilities to compete for binding to the two sites. U-69,593 and Cambridge 20 selectively displaced the high-affinity kappa site in both guinea pig and rat tissue, but were inactive at the rat-brain low-affinity site. Other kappa opioid drugs, including U-50,488, ethylketocyclazocine, bremazocine, cyclazocine, and dynormphin (1-17), competed for binding to both sites, but with different rank orders of potency. Quantitative light microscopy in vitro autoradiography was used to visualize the neuroanatomical pattern of kappa receptors in rat and guinea pig brain. The distribution patterns of the two kappa receptor subtypes of rat brain were clearly different. The pattern of rat high-affinity kappa sites paralleled that of guinea pig in the caudate-putamen, mid-brain, central gray substance of cerebrum, and substantia nigra; interspecies differences were apparent throughout most of the rest of the brain. Collectively, these data provide direct evidence for the presence of two kappa receptor subtypes; the U-69,593-sensitive, high-affinity kappa 1 site predominates in guinea pig brain, and the U-69,593-insensitive, low-affinity kappa 2 site predominates in rat brain.
Topics: Animals; Autoradiography; Binding, Competitive; Brain; Guinea Pigs; Kinetics; Rats; Receptors, Opioid; Receptors, Opioid, kappa
PubMed: 2836869
DOI: 10.1073/pnas.85.11.4061 -
Psychopharmacology 1980Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys...
Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0--17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6--17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3--3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.
Topics: Animals; Baclofen; Bemegride; Columbidae; Ethanol; Muscimol; Pentobarbital; Prejudice; gamma-Aminobutyric Acid
PubMed: 6779321
DOI: 10.1007/BF00433247