dextromethorphan and preclamol

There is increasing evidence that sigma ligands and dextromethorphan (DM) bind to at least one common high-affinity site. DM and other antitussives do not produce psychotomimetic effects. This suggested that sigma ligands may produce their characteristic effects through another site, and prompted us to review critically the literature on the side effects of sigma opiates. Contrary to what is generally accepted, the dysphoric and psychotomimetic side effects of sigma opiates are mediated by the levo-and not by the dextrorotatory isomers. Moreover, these effects are unequivocally naloxone-reversible. Therefore, the current version of the "sigma receptor", with high affinity for the dextrorotatory sigma opiates, cannot explain the psychotomimetic effects of the levorotatory enantiomers. Thus, neither the "sigma ligands" nor its newly defined "receptor" are involved in the psychotomimetic effects of sigma opiates. Further experimentation with more selective drugs and with a combination of different methods will be necessary to identify the different binding sites, and to establish their physiological role and therapeutic potential.

Topics: Animals; Dextromethorphan; Endorphins; Hallucinogens; Humans; Levorphanol; Piperidines; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Stereoisomerism

We evaluated the effects of phenytoin (DPH) on the affinity for sigma-1 (sigma(1)) receptors of agonist or antagonist sigma(1) ligands in guinea pig brain. Heterologous competition experiments showed that DPH (250 microM and 1 mM) concentration-dependently increased the affinity of the sigma(1) agonists dextromethorphan, (+)-SKF-10,047, (+)-3-PPP, and PRE-084. However, neither DPH 250 microM nor 1 mM increased (in fact, they slightly decreased) the affinity of the sigma(1) receptor antagonists haloperidol, BD 1063, NE-100, progesterone, and BD 1047. These findings suggest that allosteric modulation by DPH of the affinity of sigma(1) receptor ligands depends on the agonist or antagonist characteristics of the ligand. Therefore, determining in vitro the differential modulation by DPH of sigma(1) ligand affinity appears to constitute a procedure that can predict the pharmacological profile of different sigma(1) ligands.

Topics: Allosteric Regulation; Animals; Anisoles; Anticonvulsants; Binding, Competitive; Brain; Dextromethorphan; Drug Interactions; Ethylenediamines; Guinea Pigs; Haloperidol; Ligands; Male; Morpholines; Neurons; Phenazocine; Phenytoin; Piperazines; Piperidines; Progesterone; Propylamines; Receptors, sigma; Synaptic Transmission

1. Electrically induced contractions of the epididymal portion of rat vas deferens were potentiated in concentration-dependent manner (0.1-30 microM) by different sigma and PCP receptor ligands (PCP, TCP, (+)-MK-801, dextromethorphan and (+)-3-PPP); dextrorphan did it in a minor extent. 2. Sigma and PCP receptor ligands also potentiated the effect of noradrenaline, inducing a reduction of the noradrenaline EC50 value in the rat vas deferens. The rank order of potencies was: PCP > TCP > (+)-3-PPP > (+)-MK-801 > dextrorphan > > > dextrometorphan. 3. In contrast, haloperidol (1 microM), a sigma receptor ligand, inhibited both the neurogenic and noradrenaline-induced responses in this tissue. 4. The effect of PCP and sigma receptor ligands on noradrenaline uptake was evaluated. All compounds tested, including haloperidol, inhibited the tritiated noradrenaline incorporation to the tissue. IC50 values were in the micromolar range, between 1.09 microM for dextrophan and 18 microM for dextrometorphan. 5. It is concluded that a direct interaction with the noradrenaline uptake system is involved in the potentiating effect of some sigma and PCP receptor ligands in the epididymal portion of rat vas deferens.

Topics: Adrenergic alpha-Agonists; Animals; Dextromethorphan; Dizocilpine Maleate; Dopamine Agonists; Electric Stimulation; Excitatory Amino Acid Antagonists; Ligands; Male; Muscle Contraction; Neuroprotective Agents; Norepinephrine; Phencyclidine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Phencyclidine; Receptors, sigma; Tritium; Vas Deferens

The role of the putative sigma receptor in mediating neuroprotection against glutamate-induced neuronal injury was examined in mature cultured rat cortical neurons. With the exception of the selective sigma 1 ligand (+)-3-PPP, all of the sigma ligands tested were neuroprotective, preventing glutamate-induced morphological changes and increases in LDH release. Their rank order of neuroprotective potency (and EC50 values) was as follows: (+)-SKF 10,047 (0.81 microM) > (+)- cyclazocine (2.3 microM) > dextromethorphan (3.1 microM) = haloperidol (3.7 microM) > (+)-pentazocine (8.5 microM) > DTG (42.7 microM) = carbetapentane (46.3 microM). When corrected for relative sigma versus PCP binding affinity, it appears that a positive correlation exists between neuroprotective potency and sigma 1 site affinity. However, there does not appear to be a significant correlation between neuroprotective potency and the sigma 2 site. Critically, none of the sigma ligands were neurotoxic when tested alone at concentrations at least 5-30 times their respective neuroprotective EC50 values. Results from preliminary experiments with the selective sigma 1 ligand (+)-pentazocine indicated that sigma-mediated neuroprotection may involve the buffering of glutamate-induced calcium flux. Collectively, the results of these in vitro experiments demonstrate that sigma ligands are neuroprotective and therefore deserve further exploration as potential therapeutic agents in in vivo models of CNS injury and neurodegenerative disorders.

Topics: Animals; Calcium; Cells, Cultured; Cyclazocine; Cyclopentanes; Dextromethorphan; Glutamic Acid; Guanidines; Haloperidol; L-Lactate Dehydrogenase; Neurons; Neuroprotective Agents; Pentazocine; Phenazocine; Piperidines; Rats; Receptors, sigma

In preparation for expression studies for rat brain sigma-binding sites, Xenopus oocytes were tested for the presence of [3H]di-o-tolylguanidine (DTG)-binding sites. Native oocytes were found to contain two intrinsic [3H]DTG-binding sites, a high-affinity site (Kd = 32 +/- 6 nM, Bmax of 45.7 +/- 19 pmol/mg protein) and a low-affinity binding site (Kd = 1.3 +/- 0.7 microM, Bmax of 3.2 +/- 0.7 nmol/mg protein). In a series of radioligand-binding-displacement studies, the high-affinity binding sites were found to have a binding profile which has a similar Kd to that of the mammalian sigma 2-binding site (32 vs. 38 nM). Comparison of the IC50 values for inhibition of [3H]DTG binding in rat liver and oocytes for DTG, haloperidol (HAL), (-)-pentazocine, (+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ((+)-3-PPP), (+)-pentazocine and Zn2+, showed similarity in rank (r2 = 0.913) but a 7-fold lower potency in oocytes. These results suggest that the high-affinity [3H]DTG-binding site in oocytes represents a sigma 2-like binding site.

Topics: Animals; Binding Sites; Binding, Competitive; Carbazoles; Dextromethorphan; Female; Guanidines; Haloperidol; Liver; Mazindol; Oocytes; Pentazocine; Phenazocine; Piperazines; Piperidines; Radioligand Assay; Rats; Receptors, sigma; Xenopus laevis; Zinc

The s.c. administration of a single dose of 0.1 mg/kg of reduced haloperidol to guinea pigs produced a marked inhibition of the binding of [3H]dextromethorphan and [3H]3-(3-hydroxyphenyl)-N-(n-propyl)piperidine ([3H](+)-3-PPP) to brain. The inhibition was still evident 10 days later, and it was accompanied by residual brain levels of reduced haloperidol, and much lower levels of haloperidol. Scatchard and computer-assisted analysis demonstrated that the inhibition was due to a reduction in the number of binding sites without changes in the affinity. In the rat, haloperidol and reduced haloperidol also produced a rapid inhibition of binding to sigma sites. Interestingly, the brain of the reduced haloperidol-treated rats contained both haloperidol and reduced haloperidol, but the levels of reduced haloperidol in the haloperidol-treated rats were undetectable. However, the inhibition observed was of comparable magnitude, indicating that the haloperidol remaining in the brain is also inhibitory. In vitro experiments showed that the inhibition produced by haloperidol and reduced haloperidol was apparently competitive, but when brain membranes were preincubated with either drug, the inhibition was noncompetitive. By contrast, the inhibition produced by dextromethorphan was always competitive. Moreover, the inhibition produced by haloperidol and reduced haloperidol could not be reversed by washing. This investigation strongly suggests that the inhibition observed after the administration of haloperidol or reduced haloperidol is not a classic agonist-induced receptor down-regulation. The results indicated that the inhibition produced is a complex phenomenon, and suggest the formation of a slowly reversible or irreversible complex with reduced haloperidol or haloperidol.

Topics: Animals; Binding Sites; Brain; Dextromethorphan; Guinea Pigs; Haloperidol; Male; Oxidation-Reduction; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma

The allosteric modulation of sigma recognition sites by phenytoin (diphenylhydantoin) has been demonstrated by the ability of phenytoin to stimulate binding of various [3H] sigma ligands, as well as to slow dissociation from sigma sites and to shift sigma sites from a low- to a high-affinity state. Phenytoin stimulated the binding of the sigma 1- selective ligand [3H](+)pentazocine in a dose-dependent manner. Stimulation of binding at a final concentration of 250 microM phenytoin was associated with a decrease in the KD. The affinities of the sigma reference compounds caramiphen, dextromethorphan, dextrophan, (+)3-PPP and (+)SKF-10,047 were three- to eight-fold higher, while the affinities of benzetimide, BMY-14802, carbetapentane, DTG and haloperidol were unchanged in the presence of 250 microM phenytoin. The relative sensitivity of sigma compounds to allosteric modulation by phenytoin is not a property of all sigma ligands, and may provide an in vitro basis for distinguishing actions of sigma compounds and predicting sigma effects in vivo.

Topics: Allosteric Regulation; Animals; Binding Sites; Cyclopentanes; Dextromethorphan; Dextrorphan; Guinea Pigs; Ligands; Male; Pentazocine; Phenazocine; Phenytoin; Piperidines; Radioligand Assay; Receptors, sigma; Tritium

Dextromethorphan (DM) binds to high- and low-affinity sites in the rat brain. The high-affinity DM binding is inhibited by nonnarcotic antitussives, opipramol and sigma ligands with nanomolar affinities. Computer-assisted modeling of homologous and heterologous competition studies between DM and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] were performed at pH 8.4. These experiments confirmed the existence of the common high-affinity DM1/sigma 1 site (R1) for which DM and (+)-3-PPP have Kd values of 20 and 10 nM, respectively. DM also binds to a second high-affinity site (R2, Kd, 20 nM) for which (+)-3-PPP has only micromolar affinity. Similarly, (+)-3-PPP binds to another high-affinity site (R3, Kd, 60 nM) for which DM has micromolar affinity. The common high-affinity DM1/sigma 1 site is allosterically modulated by the anticonvulsant ropizine, and is (+)-pentazocine sensitive, as is the homologous site in the guinea pig. However, in the rat the common DM1/sigma 1 site is 10 times smaller than in the guinea pig. This explains the apparently different effects of the allosteric modifiers in both species. The multiplicity of binding sites for DM and (+)-3-PPP resolved in this investigation will help to establish the physiological role and the pharmacological potential of the different sites. Meanwhile, the pharmacological effects of DM and sigma ligands cannot be summarily attributed to any particular binding site or receptor. This investigation also demonstrates that the use of multiple labeled and unlabeled ligands, combined with computer-assisted modeling, is essential to resolve multiple binding sites with similar affinities and to characterize the complex effects of allosteric modifiers.

Topics: Allosteric Regulation; Animals; Antitussive Agents; Binding Sites; Brain; Computer Simulation; Dextromethorphan; Guinea Pigs; Hydrogen-Ion Concentration; Male; Pentazocine; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma

High-affinity binding sites (apparent KD 2.87 nM) for [3H]desmethylimipramine ([3H]DMI), have been demonstrated and characterized in membrane preparations of bovine adrenal medulla. The binding of [3H]DMI improved upon pretreatment of the membrane with KCl and was saturable, sodium dependent, and potently inhibited by nisoxetine and imipramine. [3H]DMI binding was also inhibited by various phencyclidine (PCP)- and (or) sigma-receptor ligands, with the following order of potency: haloperidol > rimcazole > (-)-butaclamol > dextromethorphan > MK-801 > (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) > PCP > N-(2-thienyl)cyclohexyl-3,4-piperidine (TCP) > (+)-SKF-10047 > (-)-SKF-10047. The inhibition produced by sigma ligands was not attributed to stimulation of either sigma 1- or sigma 2-receptors, owing to inactivity of the selective sigma-receptor ligands (+)-pentazocine and 1,3-di(2-tolyl)guanidine (DTG). The inhibition of [3H]DMI binding by sigma- and PCP-receptor ligands was not attributed to PCP1- or PCP2-receptor stimulation, owing to the decreased potency (100-fold) of these ligands in [3H]DMI assays compared with the affinity for brain PCP1 sites, and the ineffectiveness of the PCP2-ligand N-(1-(2-benzo(b)thiophenyl)cyclohexyl)piperidine (BTCP). Scatchard analysis of the inhibition by the sigma-ligands haloperidol and (+)-3-PPP, as well as the PCP1 receptor ligand MK-801, demonstrated noncompetitive interaction with the site bound by [3H]DMI. These studies indicate that bovine adrenomedullary membranes possess a specific receptor for the noradrenaline uptake inhibitor [3H]DMI, which is sensitive to allosteric modulation produced by PCP and sigma-ligands.

Topics: Adrenal Medulla; Animals; Binding Sites; Cattle; Desipramine; Dextromethorphan; Dizocilpine Maleate; Phenazocine; Phencyclidine; Piperidines; Potassium Chloride; Receptors, Opioid, delta; Receptors, Phencyclidine; Tranquilizing Agents

Pigeons were fed a fixed amount of grain-based feed and behavior was observed after administration of doses of ditolyguanidine (DTG), (+)-3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP], dextromethorphan, haloperidol, (+)-N-allylnormetazocine (NANM), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol (BMY-14802) apomorphine, pentobarbital, propranolol, and MK-801. Of the drugs tested, DTG, dextromethorphan, and (+)-3-PPP each produced dose-related increases in the percentage of pigeons exhibiting an emetic response. The emetic response produced by DTG was antagonized by haloperidol and BMY-14802 but not by propranolol. These observations suggest that the emetic response in the pigeon may be mediated by sigma sites and is unlikely to be mediated by phencyclidine receptors.

Topics: Animals; Apomorphine; Columbidae; Dextromethorphan; Dizocilpine Maleate; Dopamine Agents; Guanidines; Haloperidol; Male; Pentobarbital; Phenazocine; Piperidines; Propranolol; Psychotropic Drugs; Pyrimidines; Receptors, Opioid; Receptors, sigma; Vomiting

1. Evidence is accumulating for multiple sigma (sigma) sites in the mammalian CNS. 2. We have addressed this problem and have examined sigma site - G-protein coupling in guinea-pig and rat brain membranes. 3. Ditolylorthoguanidine (DTG), (+)-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine (3PPP) and dextromethorphan displaced [3H]-DTG (3.4 nM) with low Hill slopes of 0.5, 0.6 and 0.6, respectively in guinea-pig brain membranes. 4. In the presence of 5'-guanylylimidodiphosphate (Gpp(NH)p; 100 microM), the specific binding of [3H]-DTG was reduced by 36.7%, the Hill slope of 3PPP was increased to near unity, the ability of dextromethorphan to displace DTG was virtually abolished and the Hill slope for DTG remained low (0.7), indicating the presence of at least two binding sites. These data indicate that although Gpp(NH)p removes a dextromethorphan high affinity site, two DTG selective sites remain in the presence of Gpp(NH)p. 5. The present study suggests that DTG binds to at least three sites in guinea-pig brain membranes, at least one of which is G-protein linked. 6. In rat brain membranes, DTG displaced itself (3.4 nM) with a Hill slope near 1. 3PPP displacement of [3H]-DTG was comparable with the guinea-pig (Hill slope 0.5) and displaced from more than 1 site. Dextromethorphan did not displace [3H]-DTG at concentrations below 10 microM. 7. The heterogeneity of sigma sites appears to be less in rat than in guinea-pig brain membranes.

Topics: Animals; Binding, Competitive; Brain Chemistry; Dextromethorphan; Dopamine Agents; GTP-Binding Proteins; Guanidines; Guinea Pigs; In Vitro Techniques; Male; Membranes; Piperidines; Radioligand Assay; Rats; Rats, Wistar; Receptors, Opioid, delta

Computer-assisted, simultaneous analysis of self- and cross-displacement experiments demonstrated the existence of several binding sites in guinea pig brain for dextromethorphan, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), and 1,3-di-o-tolyl guanidine (DTG). Dextromethorphan binds with high affinity to two sites (R1 Kd 50-83 and R2 Kd 8-19 nM) and with low affinity to two additional sites (R3 and R4). (+)-3-PPP binds to one high-affinity (R1 Kd 24-36 nM), to one intermediate-affinity (R3 Kd 210-320 nM), and to two (R2 and R4) low-affinity sites. DTG binds with almost identical high affinity to two different sites (R1 Kd 22-24 and R3 Kd 13-16 nM). These results confirm that dextromethorphan, (+)-3-PPP, and DTG bind to the common DM1/sigma 1 site (R1). The binding of DTG to two different sites with identical affinities precludes the use of this compound as a specific marker for sigma receptors. Besides, haloperidol displaces labeled ligands from both high-affinity DTG sites (R1 and R3) with high affinity. Thus, haloperidol sensitivity should not be used as the single criterion to identify a putative receptor. The resolution of these novel sites also may provide new insights into the multiple effects of antipsychotic drugs. In addition, this investigation has important implications regarding the methods that must be applied to characterize multiple binding sites and their relations with putative receptors.

Topics: Animals; Binding Sites; Binding, Competitive; Brain; Computer Simulation; Dextromethorphan; Guanidines; Guinea Pigs; Haloperidol; Kinetics; Male; Models, Biological; Piperidines; Receptors, Opioid; Receptors, sigma; Tritium

The interaction of various compounds with sigma binding sites was examined in membranes prepared from whole guinea pig brain. Whereas [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine labeled a single population of binding sites exhibiting a Kd of 43 nM, [3H]1,3-di-o-tolylguanidine bound to two sites having Kds of 35 and 212 nM, and to a greater maximum number of sites than [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. Haloperidol, 1,3-di-o-tolylguanidine, BMY 14802, and (-)-pentazocine each displayed nearly equal affinity for binding sites labeled by [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [3H]1,3-di-o-tolylguanidine, whereas (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine was 3 times more potent in inhibiting [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine binding. In contrast, (+)-SKF 10,047, (+)-cyclazocine and (+)-pentazocine exhibited more than 9-fold higher affinity for [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine binding sites. Dextromethorphan was 15-fold more potent against [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine, inhibited [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding in a biphasic manner, and inhibited [3H]haloperidol and [3H](+)-SKF 10,047 binding with potencies similar to those obtained against [3H]1,3-di-o-tolylguanidine and [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, respectively. Phenytoin increased [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [3H](+)-SKF 10,047 binding, but did not enhance [3H]1,3-di-o-tolylguanidine or [3H]haloperidol binding. However, the potency of dextromethorphan to inhibit [3H]1,3-di-o-tolylguanidine binding was increased in the presence of phenytoin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Binding, Competitive; Brain; Dextromethorphan; Dopamine Agents; Guanidines; Guinea Pigs; Haloperidol; In Vitro Techniques; Kinetics; Membranes; Phenazocine; Phenytoin; Piperidines; Receptors, Opioid; Receptors, sigma

Topics: Animals; Binding Sites; Dextromethorphan; Guinea Pigs; Hallucinogens; Haloperidol; In Vitro Techniques; Kinetics; Levorphanol; Piperidines; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma

Computer-assisted analysis of self- and cross-displacement studies between dextromethorphan (DM) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine ((+)-3-PPP) demonstrated in the rat brain the existence of two high-affinity and one low-affinity binding site for each ligand. One high-affinity site is the common DM1/sigma 1 site, the affinity of which is allosterically increased 4 to 5-fold by 10 microM ropizine. The Kd values of the DM1/sigma 1 for DM and (+)-3-PPP are 17 and 11 nM respectively. DM binds to the second high-affinity site (R2) with a Kd of 15 nM; this site has low affinity for (+)-3-PPP. Conversely, (+)-3-PPP binds with high affinity (Kd 53 nM) to another site (R3), that has low-affinity for DM. The Bmax of the common DM1/sigma 1 site in the rat is about ten times smaller than that in the guinea pig. Thus, extreme caution should be exercised in extrapolating from one species to another. Since DM and most sigma ligands bind to more than one site, not all of which are shared, it is important not to attribute the complex pharmacological effects of these ligands to a single hypothetical receptor.

Topics: Allosteric Site; Animals; Binding, Competitive; Brain; Dextromethorphan; Electronic Data Processing; In Vitro Techniques; Kinetics; Models, Biological; Pentazocine; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Tritium

Topics: Allosteric Regulation; Animals; Autoradiography; Binding Sites; Brain; Dextromethorphan; Guinea Pigs; In Vitro Techniques; Levorphanol; Piperazines; Piperidines; Tissue Distribution

Equilibrium binding analysis demonstrated that (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-[3H]3-PPP] binds in guinea pig brain homogenates to high and low affinity sites with Kd values of 25 nM and 0.9 microM, respectively. Competition studies with dextromethorphan (DM) site ligands and other drugs against (+)-[3H]3-PPP demonstrated that their Ki values and rank order of potency are identical to those found previously against [3H] DM. Most significant, ropizine produced a concentration-dependent increase in the binding of (+)-[3H]3-PPP, with an inhibitory component at high concentrations, as described previously for [3H]DM. Similarly, phenytoin increased the binding of (+)-[3H]3-PPP in the same fashion as that of [3H]DM. Computer-assisted analysis of equilibrium binding of (+)-[3H]3-PPP in the presence of 10 microM ropizine demonstrated that the binding increase produced is due to a 3-fold increase in the affinity for (+)-[3H]3-PPP. These results, and our previous finding that sigma ligands inhibit [3H] DM binding with a rank order of potency similar to that for sites labeled with (+)-[3H]3-PPP or (+)-[3H]SKF10,047 strongly suggest that sigma ligands bind to the high affinity DM site. These findings, and the inability of DM and other antitussives to produce psychotomimetic side effects, suggest that the high affinity DM sites can mediate only the nonpsychotomimetic effects of sigma ligands. However, further studies are necessary to determine the physiological role and therapeutic potential of the DM high affinity sites.

Topics: Allosteric Regulation; Animals; Binding Sites; Binding, Competitive; Dextromethorphan; Guinea Pigs; In Vitro Techniques; Levorphanol; Phenytoin; Piperazines; Piperidines; Receptors, Opioid; Receptors, sigma