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PubMed1998

Properties of mu 3 opiate alkaloid receptors in macrophages, astrocytes, and HL-60 human promyelocytic leukemia cells.

An opiate alkaloid-selective receptor, designated mu(3), mediates inhibition by morphine of activation of human peripheral blood monocytes and granulocytes. The mu(3) receptor is present on several macrophage cell types including microglia, on cultured astrocytes, and in brain and retina. Murine macrophage cell lines and human HL-60 leukemia cells contain high concentrations of these receptors. Binding of 3H-morphine to the receptor is displaced by morphine, etorphine, naloxone, diprenorphine and morphine 6-glucuronide, but not by morphine 3-glucuronide, fentanyl, benzomorphans, enkephalins, dynorphin, beta-endorphin, endomorphin-1, other opioid peptides or nociceptin (orphanin FQ). The mu(3) receptor appears to be much more sensitive to inactivation by reduced glutathione than are classical mu, delta and kappa receptors. Evidence is also presented for G protein-coupling of these receptors. These and other data raise the possibility that the mu(3) receptor is a member of a chemokine or of another related receptor family, rather than the opioid receptor family. The affinity for morphine of mu(3) receptors of granulocytic-differentiated HL-60 cells is markedly enhanced in the presence of levorphanol and certain benzomorphans. In contrast, receptors of monocytes, macrophage cell lines, microglia, macrophage-differentiated HL-60 cells and astrocytes are not affected by levorphanol or benzomorphans. It is concluded that mu(3) receptors of granulocytic and promyelocytic cells differ from those of macrophage and astrocyte cell types, possibly due to differences in receptor subtype or to the presence of an additional component in the granulocytic and promyelocytic cells.

Animals↗
PubMed1989

Evidence for a multi-site model of the rat brain sigma receptor.

Irradiation of rat brain membranes with light of 254 nm, a treatment which modifies ultra-violet absorbing residues in proteins, decreased binding of both [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([ 3H](+)-3-PPP) and [3H]1,3-di-o-tolylguanidine ([3H]DTG) to sigma receptors. For [3H](+)-3-PPP, this was due to a decreased Bmax. In contrast, irradiation markedly increased binding of [3H](+)-N-allylnormetazocine ([3H](+)-SKF 10,047) due to a decrease in the Kd. Both unlabeled DTG and haloperidol were competitive inhibitors of [3H](+)-3-PPP binding to untreated membranes, causing an increase in the Kd and no change in the Bmax. The benzomorphans, (+)-SKF 10,047 and (+)-pentazocine, were uncompetitive inhibitors, causing a decrease in both the Kd and Bmax for [3H](+)-3-PPP. Finally, the ability of DTG and (+)-3-PPP to inhibit binding of [3H](+)-SKF 10,047 was markedly reduced by ultra-violet irradiation, whereas irradiation had little effect on the potency of unlabeled (+)-SKF 10,047 and (+)-pentazocine. These data suggest that sigma-related (+)-benzomorphans and non-benzomorphans interact either with distinct, allosterically coupled sites on the same sigma receptor macromolecule or with different populations of sigma receptor types.

Animals↗
PubMedDate not supplied

Classification of opioids on the basis of their ability to antagonize bombesin-induced grooming in rats.

Bombesin (0.001-0.125 microgram) elicits dose-related excessive grooming when administered i.c.v. to rats. In contrast to the grooming produced by various other endogenous and exogenous agents, bombesin-induced grooming is not markedly affected by behaviorally non-depressant doses (determined by a novel method) of morphine (3 and 10 mg/kg, s.c.). The benzomorphan, ethylketocyclazocine (0.25-0.5 mg/kg, s.c.), does attenuate bombesin-induced grooming in a dose-related and stereospecific manner. In this study, we have classified 27 opioids on the basis of their ability to antagonize bombesin-induced grooming. The results of the classification indicate that a benzomorphan nucleus is required for activity in this test. Our test provides evidence that postulated benzomorphan binding sites are functionally active as pharmacologic receptors.

Animals↗
PubMed1983

Ketazocines and morphine: effects on gastrointestinal transit after central and peripheral administration.

The mu agonist, morphine, and the prototype kappa agonists, ketocyclazocine and ethylketocyclazocine (EK), were studied for their effects on gastrointestinal transit. Following s.c. administration, both morphine (0.3-3 mg/kg) and ketocyclazocine (0.3-10 mg/kg) antagonized transit of an opaque marker through the small intestines of mice. Morphine (0.1-1 microgram) was also effective after intracerebroventricular (icv) administration in mice whereas ketocyclazocine (0.3-30 micrograms) was not. Similarly, while both morphine (0.3-5 mg/kg) and EK (0.6-10 mg/kg) slowed transit after s.c. injection to rats, only morphine (1-10 micrograms), but not EK (0.3-300 micrograms), was active following icv administration. Icv infusion of the mu benzomorphan, phenazocine (10-100 micrograms), slowed transit in a dose-related manner. These results indicate that there may be an anatomically distinct distribution of receptors for benzomorphan kappa agonists in both the mouse and rat, with these opiate receptors not being located near the lateral cerebral ventricles. The difference in efficacy between morphine and ketazocines in slowing gastrointestinal transit after icv administration to rodents suggests that (a) inactivity in this endpoint is a characteristic of benzomorphan kappa compounds and (b) the model may serve as a useful screen when establishing in vivo profiles of kappa agonists in mice and rats.

Animals↗
PubMed2000

Kappa opioid agonists as targets for pharmacotherapies in cocaine abuse.

Kappa opioid receptors derive their name from the prototype benzomorphan, ketocyclazocine (1a) which was found to produce behavioral effects that were distinct from the behavioral effects of morphine but that were antagonized by the opioid antagonist, naltrexone. Recent evidence suggests that agonists and antagonists at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. Kappa agonists blocked the effects of cocaine in squirrel monkeys in studies of cocaine discrimination and scheduled-controlled responding. Studies in rhesus monkeys suggested that kappa opioids may antagonize the reinforcing effects of cocaine. These studies prompted the synthesis and evaluation of a series of kappa agonists related to the morphinan, L-cyclorphan (3a) and the benzomorphan, L-cyclazocine (2). We describe the synthesis and preliminary evaluation of a series of morphinans, structural analogs of cyclorphan 3a-c, the 10-keto morphinans 4a and b, and the 8-keto benzomorphan 1b, structurally related to ketocyclazocine (1a). In binding experiments L-cyclorphan (3a), the cyclobutyl (3b), the tetrahydrofurfuryl 3c and the 10-keto 4b analogs had high affinity for mu (mu), delta (delta) and kappa (kappa) opioid receptors. Both 3a and 3b were more selective for the kappa receptor than the mu receptor. However, 3b was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only a 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. The cyclobutyl compound 3b was found to have significant mu agonist properties, while 3a was a mu antagonist. All compounds were also examined in the mouse tail flick and writhing assay. Compounds 3a and 3b were kappa agonists. Correlating with the binding results, compound 3a had some delta agonist properties, while 3b was devoid of any activity at the delta receptor. In addition, compounds 3a and 3b had opposing properties at the mu opioid receptor. The cyclobutyl compound 3b was found to have significant mu agonist properties, while 3a was a mu antagonist.

Analgesics, Opioid↗
PubMed1991

Binding of substituted and conformationally restricted derivatives of N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane at sigma-receptors.

Certain benzomorphans, such as N-allylnormetazocine, are classical "sigma-opiates" that bind both at sigma and phencyclidine (PCP) binding sites with modest affinity. Recently, we identified N-substituted 2-phenylaminoethane as being the primary sigma-pharmacophore of the benzomorphans and demonstrated that 1-phenyl-2-aminopropane (2) derivatives, depending upon their terminal amine substituents, constitute a novel class of high-affinity sigma-selective agents. With this pharmacophore, it is shown in the present investigation that the aromatic hydroxyl group (a prime feature of all the sigma-opiates) contributes little to the binding of 2 at sigma-sites. It is also demonstrated that an N-substituted aminotetralin moiety (such as 17, a conformationally restricted analogue of 2) may also be considered a sigma-opiate pharmacophore. Unlike the sigma-opiates, derivatives of 2 and 17 display no affinity for PCP sites and must consequently lack those structural features important for the binding of benzomorphans at PCP sites. Because 3-phenylpiperidines and related sigma-ligands also possess a phenylalkylamine imbedded within their structures, we propose that the 2-phenylaminoethane moiety is a common sigma-pharmacophore for derivatives of 2, the 3-phenylpiperidines, and the sigma-opiates.

Animals↗
PubMed2000

Modeling of kappa-opioid receptor/agonists interactions using pharmacophore-based and docking simulations.

The interaction of the kappa-opioid receptor with arylacetamide and benzomorphan derivatives acting as agonists was modeled through pharmacophore-based and docking calculations. Potentially bioactive conformations of representative ligands (U-50,488 and its benzo-fused analogues 4 and 6 for arylacetamides and MPCB for benzomorphans) were identified by systematic conformational analysis and docked into a 3D model of the kappa-receptor. The obtained complexes, refined by energy-minimization and molecular dynamics, were evaluated for their consistency with structure-activity relationships and site-directed mutagenesis data. The following interactions are hypothesized to govern the ligand-receptor recognition process: (i) a salt bridge between the Asp138 carboxylate and the protonated nitrogen of the bound agonist; (ii) a hydrogen bond donated by the Tyr312 hydroxyl to the carbonyl oxygen of arylacetamides and MPCB; (iii) hydrophobic interactions established by the dichlorophenyl moiety of arylacetamides and the pendant phenyl ring of MPCB with the surrounding side chains of Tyr312, Leu224, Leu295, and Ala298; (iv) a pi-stacking contact between the Tyr312 side chain and the phenyl ring of arylacetamides; (v) a hydrogen bond linking the His291 imidazole ring to the phenolic hydroxy group featured by typical benzomorphans and the arylacetamides 4 and 6.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2000

Partial opioids. Medications for the treatment of pain and drug abuse.

Pentazocine and cyclazocine are two benzomorphans that were synthesized by the late Sydney Archer in 1962. These benzomorphans were synthesized as part of an effort to develop analgesics with little or no abuse potential. Pentazocine is used as an analgesic, often in individuals who have sever pain or in those who have drug-abuse problems. Cyclazocine is a low-liability analgesic and potential therapeutic for the treatment of drug abuse. The risk of drug dependence is lower with the benzomorphans, which usually act as partial agonists at the mu opioid receptor and as kappa agonists. In an attempt to synthesize analogs of cyclazocine with increased bioavailability and varying kappa agonist and partial mu agonist properties, a series of 8-amino derivatives of cyclazocine were synthesized. These compounds were characterized in radioligand binding assays for their affinity and selectivity for the mu, delta, and kappa opioid receptors. Mouse antinociceptive tests were used to characterize the agonist and antagonist properties of each compound at the mu, delta and kappa receptors.

Analgesics↗
PubMed1975

The synthesis and pharmacology of a new analgesic, ID-1229.

A new non-narcotic analgesic, 2-[3-(p-fluorobenzoyl)-n-propy]-5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan (ID-1229) has been prepared from 5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan. The analgesic activities of ID-1229 were several times more potent than those of pentazocine in the acetic acid writhing test in mice, bradykinin test in rats, Randall-Selitto's test in rats, and the electrical stimulation test in mice, while, ID-1229 showed little activity in both the tail pinch test and the hot plate test. ID-1229 did not show anti-narcotic activity in the morphine-combined test, and the Straub tail phenomenon was not observed in ID-1229. ID-1229 showed CNS activities in some tranquilizing tests, but did not show activity in several other CNS tests. The CNS potency is condiserably weaker as compared with haloperidol or diazepam, and the pattern of CNS activities in ID-1229 is quite different from those of both compounds. ID-1229 is a potent non-narcotic analgesic with tranquilizing activity, which is quite free from the undersirable side effects of morphine or morphine-like compounds including pentazocine.

Analgesics↗
PubMed1985

Opiate binding sites in the chick, rabbit and goldfish retina.

The characteristics of opiate binding sites in the retina of the chick, rabbit and goldfish have been investigated. In the newly hatched chick retina, 131 fmol/mg of binding sites for [D-Ala2-D-Leu5]-[3H]enkephalin are present; competition studies with the delta selective peptide [D-Thr-Leu5]-enkephalin (DTLET) and the mu selective peptide morphiceptin show that all of the [D-Ala2-D-Leu5]-[3H]-enkephalin binding sites are of the delta subtype. Dihydro[3H]morphine binds poorly to the chick retina; 13.2 fmol/mg of this binding is displaceable by morphiceptin and corresponds to mu binding sites. Benzomorphan sites are defined as sites occupied by [3H]diprenorphine which is displaceable by low concentrations of ethylketocyclozacine but not by high concentrations of D-Ala2-D-Leu5-enkephalin and morphiceptin. At least 88 fmol/mg of benzomorphan sites are present in the chick retina. [3H]diprenorphine binding to the rabbit and fish retina was measured. The rabbit retina bound 60 fmol/mg, and the fish retina 42 fmol/mg of [3H]diprenorphine. These findings are discussed in the light of the studies on the localization and physiological effects of enkephalin in the retina.

Animals↗
PubMed1985

Stereospecific opiate receptors in the actions of thyrotropin releasing hormone and morphine on gastrointestinal transit.

Studies in these laboratories have shown that morphine and thyrotropin releasing hormone (TRH) inhibit gastrointestinal transit in the mouse. Administration of morphine sulfate (5 mg/kg, s.c.) or TRH (10 microgram i.c.v.) to mice inhibited gastrointestinal transit as measured by the charcoal meal test. In order to determine whether the effects of TRH and morphine were mediated via stereospecific opiate receptors, the effects of two stereoisomers of an antagonist, (-) alpha -5,9-diethyl-2'-hydroxy-2-(3-furylmethyl)6,7-benzomorphan (MR2266), the active isomer and (+) alpha-5,9-diethyl-2'-hydroxy-2-(3-furylmethyl)6,7-benzomorphan (MR 2267), the inactive isomer, on morphine and TRH induced changes in gastrointestinal transit were determined. Morphine and THR induced inhibition of gastrointestinal transit was antagonized by MR 2266 (1 and 3 mg/kg, s.c.) but was unaffected by MR 2267. These studies provide evidence for the involvement of opiate receptors in the actions of morphine and TRH on gastrointestinal transit, and further suggest that the receptors are stereospecific in nature.

Animals↗
PubMed1990

Sigma binding sites in the brain; an emerging concept for multiple sites and their relevance for psychiatric disorders.

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.

Animals↗
PubMed1990

Drug specificity of pharmacological dystonia.

Three (+)-benzomorphans that bind to sigma receptors produced dystonia in a dose-related manner when microinjected into the red nucleus of rats. Two lines of evidence suggest that these effects were related to the sigma-binding properties of the compounds. First, the behavioral potency of the (+)-benzomorphans and other active sigma compounds correlated highly with their affinities for [3H]1,3-di-o-tolylguanidine-labelled sigma receptors in the rat brain (r = .94). Second, similar intrarubral injections of non-sigma ligands were without effect: various vehicles, a structurally related (+)-opiate with no affinity for sigma receptors, and selective dopaminergic and serotonergic compounds failed to significantly alter the normal posture of rats. The only ligand in this study that binds with high affinity to sigma receptors, but failed to elicit torsional head movements was (+)-[3-(3-hydroxyphenyl)-N-(1-propyl)piperidine] [(+)-3PPP], a ligand with mixed activity at sigma and dopamine receptors. Since (+)-3PPP failed to produce an effect on its own and also failed to attenuate the dystonia produced by another sigma ligand (DTG), it may interact with a non-sigma mechanism or with a different sigma receptor type from the other compounds.

Animals↗
PubMed1977

Application of the Free-Wilson technique to structurally related series of homologues. Quantitative structure-activity relationship studies of narcotic analgetics.

A series of benzomorphans with ED50 values determined in vivo by the hot-plate method in mice is analyzed by the modified Free-Wilson method. The QSAR yields 36 substituent constants (ai) with contributions to the overall activity in agreement with experimental data. Substituent constant values obtained for benzomorphans are used in calculating log (1/C) values for six morphinans. An excellent correlation is obtained (r = 0.95) between the six calculated and observed activities. The possibility of extending the Free-Wilson approach from one series of homologues to another is demonstrated.

Analgesics, Opioid↗
PubMed1986

1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs.

Brain sigma-type receptors are thought to mediate hallucinogenic effects of certain benzomorphan opiates in humans. The biochemical characterization of sigma receptors has been difficult because of the lack of potent and selective ligands. We report here the synthesis and characterization of a tritiated, symmetrically substituted guanidine derivative, 1,3-di(2-[5-3H]tolyl)guanidine ([3H]Tol2Gdn), that binds with high affinity to a single population of binding sites in guinea pig brain membrane preparations. The [3H]Tol2Gdn binding site displays stereoselectivity for dextrorotatory optical isomers of benzomorphan opiates known to have sigma-type behavioral effects. Furthermore, the [3H]Tol2Gdn binding site has a high affinity for haloperidol and for phenothiazine antipsychotics, which have antihallucinatory properties in humans. The drug-selectivity profile of [3H]Tol2Gdn binding closely correlates with the drug-selectivity profile of tritiated (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [+)-[3H]3-PPP) binding to guinea pig brain membrane receptors. (+)-[3H]3-PPP has been proposed to be a selective sigma-receptor ligand [Largent, B. L., Gundlach, A. L. & Snyder, S. H. (1984) Proc. Natl. Acad. Sci. USA 82, 4983-4987]. Receptor autoradiography using [3H]Tol2Gdn on slide-mounted rat and guinea pig brain sections reveals a heterogeneous distribution pattern of enriched binding in limbic and sensorimotor structures of the brain. These results indicate that [3H]Tol2Gdn is a selective ligand for the sigma-site. Availability of this sigma-receptor probe should greatly facilitate the physiological, biochemical, and pharmacological characterization of sigma receptors in brain.

Animals↗
PubMed1976

[Study on novel morphine antagonists in the animal experiment (author's transl)].

The morphine-antagonistic properties of 5 novel compounds, (--)N-(3-Furylmethyl)-nordesomorphine-hydrochloride-monohydrate (Wa 494-Cl), (--)N-(3-Furylmethyl)-3-hydroxy-morphinan-methansulfonate (Mr 1257 MS), (--)2-(3-Furylmethyl)-2'-hydroxy-5,9alpha-dimethyl-6,7-benzomorphan-methansulfonate (Mr 1452 MS), (+/-)-2-(3-Furylmethyl)-2'-hydroxy-5,9alpha-diethyl-6,7-benzomorphan-hydrochloride (Mr 1302 MS), (--)-N-(3-Furylmethyl)-noroxymorphon-methanesulfonate (Mr 1767 MS), have been examined with different methods on mice and cats. Their properties have been compared with those of naloxone, cyclazocine and nalorphine. The new test compounds showed a profile of action like naloxone.

Analgesia↗
PubMed1989

Sigma receptors regulate contractions of the guinea pig ileum longitudinal muscle/myenteric plexus preparation elicited by both electrical stimulation and exogenous serotonin.

Sigma receptors are specific, highly localized binding sites in limbic and sensorimotor structures of the brain that interact with many psychotropic drugs. These agents include the psychotomimetic benzomorphan opiates, the psychotomimetic drug phencyclidine and its analogs, as well as numerous typical and atypical antipsychotics such as haloperidol, chlorpromazine, and the novel drugs BMY 14802 and rimcazole. So far, no physiological function has been assigned to these binding sites. We have synthesized a number of novel sigma receptor-active drugs derived from the selective sigma ligand N,N'-di(o-tolyl)guanidine (DTG). DTG and its congeners were found to inhibit contractions of the guinea pig ileal longitudinal muscle/myenteric plexus (LMMP) preparation evoked by electrical stimulation. In addition, the sigma ligands noncompetitively antagonized contractions of the LMMP preparation evoked by serotonin (5-HT). The 5-HT-evoked contractions were found to be largely due to 5-HT's activation of 5-HT3 receptors to release ACh. The activity of DTG congeners in inhibiting electrically or 5-HT-evoked contractions of the LMMP highly correlated with their potency to inhibit binding of both 3H-DTG and (+)3H-3-PPP [3(3-OH-phenyl)-N-(1-propyl)piperidine] to sigma receptors in guinea pig brain homogenates. Two DTG congeners that did not bind to sigma receptors also showed no activity in the bioassay. Many other (but not all) sigma receptor ligands showed a high correlation between their potency to inhibit electrically evoked contractions of the LMMP and their sigma receptor binding affinity. The benzomorphans (+)SKF 10,047 and (+)cyclazocine potentiated electrically evoked contractions of the LMMP. Sigma ligands also inhibited the contractions of the LMMP in the presence of the opiate antagonist naloxone and in preparations in which opioid receptors had been inactivated by treatment with the irreversible opiate antagonist beta-chlornaltrexamine. Control experiments suggested that the sigma ligands act via a neuronal mechanism to inhibit ACh release evoked by electrical stimulation or by stimulation with 5-HT. These results suggest that there are functional sigma receptors on cholinergic nerve terminals or within the myenteric plexus and that these receptors can inhibit stimulated ACh release through an opioid receptor-independent mechanism. However, sigma receptor activation in the ileum has the same effect on ACh release as activation of naloxone-sensitive opioid receptors. The LMMP may be an in vitro bioassay system for characterizing the mechanism of action of sigma receptors and for determining the biological efficacy of drugs known to bind to sigma receptors in radioligand binding assays.

Animals↗
PubMed1984

Kappa opiate receptor agonists: effects on behavior and on brain function and structure in rhesus monkeys.

In the present study several drugs that are predominantly agonists of kappa receptors were tested in rhesus monkeys prepared with deep and surface brain electrodes. The administration of two benzomorphan derivatives and of ethylketocyclazocine induced acute behavioral effects resembling catatonia concomitant with generalized spike and slow-wave electroencephalographic activity at widespread brain sites, that lasted for about 1 hr. After administration of one to three doses of these agonists (the benzomorphan derivatives to five monkeys and the ethylketocyclazocine to two monkeys), chronic recording changes developed, characterized by continuous high-amplitude spiking activity focal at the anterior septal region and periaqueductal gray of the mesencephalon. They increased in intensity with the passage of time, the monkeys having been followed as long as 5 months without further drug administration. Light microscopy and electron microscopy showed no structural abnormalities in the monkey brains at the sites of altered recordings, although occasional dendritic atrophy was noted at all cortical and subcortical brain sites examined. Chronic recording changes did not develop in a monkey that received U-50,488H on eight occasions. And none of the electrode-implanted monkeys that served as controls (having received no kappa agonists) developed recording changes. The sites affected by the active kappa agonists were those at which abnormal activity has been correlated with psychotic behavior. The ability of the kappa agonists to induce a lasting physiologic change without corresponding structural change at those focal sites implicated in schizophrenia may prove a useful probe in further investigations into the cause of schizophrenia and its ultimate treatment.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗