Tricyclic Neuroleptics Research Articles

Abstract A48: Therapeutic reactivation of the protein phosphatase 2A (PP2A) for the treatment of KRAS-driven cancers

Abstract There have been tremendous strides in the development of therapies for the treatment of NSCLC over the past decade. Nevertheless, the most common recurrent mutation driving the growth of NSCLC, mutant KRAS, accounting for ~25% of patients with advanced NSCLC, remains without an effective therapy. Thus, novel therapies are critically needed to improve the lives of patients suffering from KRAS-driven lung cancers. Protein phosphatase 2A (PP2A) is a serine threonine-directed tumor-suppressive phosphatase that is dysregulated and deactivated in cancer by multiple mechanisms including somatic mutation, suppression of individual subunits, increased expression of endogenous PP2A inhibitors and changes in post-translational modifications to the catalytic C subunit. Given its central role in regulating many key cellular processes and its role in human disease pathogenesis, many efforts have been developed to therapeutically target PP2A. Our group has developed first-in-class direct small-molecule activators of PP2A (SMAPs) by using the chemical scaffold of the FDA-approved tricyclic neuroleptics. We have used molecular modeling, hydroxyl radical footprinting and cryo-electron microscopy to structurally resolve the mechanism of action of SMAP-mediated growth suppression. Specifically, SMAPs protect the regulatory c-terminal tail of the catalytic subunit through changes in the methylation of the terminal leucine (L309) that induces the holoenzyme heterotrimerization and increased substrate-directed catalysis. SMAP treatment of KRAS-mutant lung cancer cells induced apoptosis and decreased the phosphorylation of PP2A targets including AKT and ERK. We found that treatment of xenograft, PDX, and GEMM mouse models of KRAS-mutant lung cancer cells with SMAPs resulted in marked tumor growth inhibition. Taken together, these studies demonstrate the potential of using SMAPs as an approach to treat KRAS-mutant NSCLC. We also established that PP2A activity defines the response of KRAS-mutant lung cancer cells across library of over 200 kinase inhibitors. In vivo studies using xenograft mouse models of KRAS-mutant lung adenocarcinoma demonstrated that SMAP in combination with MEK inhibitor resulted in tumor regression. Our studies have identified a combination of drugs that is effective in vivo for the treatment of KRAS-mutant lung cancer. Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other KRAS-driven cancers and represents a first step into a new territory of developing small-molecule activators of tumor-suppressor proteins. Citation Format: Jaya Sangodkar, Jukka Westermarck, Derek Taylor, Goutham Narla. Therapeutic reactivation of the protein phosphatase 2A (PP2A) for the treatment of KRAS-driven cancers [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A48.

Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A.

Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.

The structure of psychotropic drugs (including theoretical prediction of a new class of effective neuroleptics)

A brief introductory review is presented of the etiology of affective disorders, the neuropsychopharma-cological modalities used in treating these states, and the mechanisms by which these therapies act. The topological and topographical requisites for effective neuroleptic (antipsychotic) drugs (the major tranquillizers) are outlined. Quantum chemical results, both CNDO/2 and INDO, are presented for promazine, perazine, and their CI and CF3 derivatives. Application of the topographical postulates led us to perform quantum chemical calculations on a series of hitherto unsynthesized and untested compounds, N-piperdinopromazines. We predicted these would be effective neuroleptics. In the interim a compound of this type was synthesized and tested and it is, indeed, a major tranquillizer. The subtle differences in geometrical conformation between tricyclic neuroleptics (which are postsynaptic dopamine blockers) and the closely related tricyclic antidepressants (which inhibit reuptake of norepinephrine and serotonin back into the the presynapse) are indicated. In the area of hallucinogens or psychotomimetic agents, it is emphasized that even though compounds like LSD and mescaline exhibit cross tolerance, they apparently do not act by the same mechanism. Thus the commonalities in structures between these two groups previously invoked by other authors merit reexamination and a sharpening of focus. Quantum chemical results, CNDO/2 and PCILO, are presented for a few of these compounds whose crystal structures have been determined recently. Our interest in these psychotomimetics was twofold; first, because of their intrinsic interest in the hierarchy of psychotropic drugs and second, to gain insight into why many narcotic antagonists are undesirably psychotomimetic.

Comparison of the Chromatographic Behavior of Tricyclic Neuroleptics on Calixarene-Bonded, Monolithic and Conventional RP-HPLC Columns

The effect of different chromatographic conditions, such as buffer concentration and type of organic modifier, on the retention behavior of nine tricyclic neuroleptics on three different RP-HPLC columns was investigated. Two recently developed columns, calixarene-bonded (CALTREX) AIII) and monolithic (Chromolith) Performance RP-18e) columns, were compared with a conventional RP-C18 HPLC column (LiChrospher). The results showed how the mobile phase conditions had different effects on the analyte retention on these three columns. For example, the elution order of some analytes and the initiation of separation of the geometric isomers of the three analytes--which have E/Z-isomers (cis/trans-isomers)--could be altered by changing the conditions and the column type. Under identical conditions, a calixarene-bonded phase was the best for this separation, a monolithic phase gave comparable results and the conventional RP-column was the least effective. Concerning the geometric isomers separation, the Chromolith Performance RP-18e was superior.

Stand der Pharmakogenetik in der klinischen Arzneimitteltherapie

Individual differences in the effect and side effect of drugs are partly due to genetic factors (genetic polymorphisms). The responsible polymorphisms lie in genes encoding for drug metabolism and transport but also in direct and indirect drug targets. While genetic variants in pharmacokinetic structures exert effects on drug efficacy via the differences in drug exposure, polymorphisms in drug targets can directly affect clinical efficacy and may lead to a broad variation spectrum between inefficacy and severe side effects. However, at present, our knowledge on genetic variants in drug targets is less detailed than the knowledge on pharmacogenetic variability within drug metabolism. A goal of pharmacogenetic diagnostics implemented in clinical practice is to better predict the individual drug effects on the basis of molecular-genetic profiles. Therapy recommendations can be given as dose adjustments, in particular in the case of polymorphisms of drug metabolizing enzymes which will lead to less variable drug concentrations. At present there are few examples of the application of pharmacogenetic tests in Germany in order to improve and individualize drug therapy. The reasons for this are multifold. On the one hand it is due to the limited awareness of pharmacogenetics; on the other hand it may be due to the lack of fast and economical availability of the appropriate laboratory tests. The most important reason, however, may be that most results of pharmacogenetic research are so far not translated into therapeutically usable conclusions and therapy recommendations. Thus, testing for a genotype without concrete consequences for the drug therapy of an individual patient does not make sense. Pharmacogenetic research, thereby, stands in many cases at the threshold to clinical applicability and in many cases, for instance for the genotyping for thiopurine methyltransferase polymorphisms prior to azathioprine therapy or of dihydropyrimidine dehydrogenase polymorphisms prior to treatment with 5-fluorouracil, as well as for diagnostics of CYP2D6 before therapy with certain tricyclic antidepressants and neuroleptics, one would ask already today whether a such drug therapy is still responsible without pharmacogenetic diagnostics.

In Vitro Antiproliferative Effects of Neuroleptics, Antimycotics and Antibiotics on the Human Pathogens Acanthamoeba polyphaga and Naegleria fowleri

Using reproducible conditions in vitro, the aim of this study was to obtain a comparative evaluation of the efficacies of several tricyclic neuroleptics, antimycotics and antibiotics with antiproliferative activities against Acanthamoeba polyphaga and Naegleria fowleri trophozoites. We used reproducible conditions in vitro to obtain results. In the case of A.polyphaga, the tricyclic neuroleptics trifluoperazine and chlorpromazine had the best inhibitory (IC50) effects followed by mepacrine, ketoconazole, pentamidine, miconazole, amphotericin B, and metronidazole. Of all, rifampicin was the least effective. Mepacrine was the most effective compound with the minimum inhibitory concentration (MIC100) against A.polyphaga [corrected] The most effective drugs against N. fowleri expressed as (IC50) were as follows: the antimycotics ketoconazole and amphotericin B, followed by trifluoperazine, mepacrine, chlorpromazine, miconazole, and metronidazole. The least effectives were rifampicin and pentamidine. The most potent growth inhibitors (MIC100) against N. fowleri were the antimycotics amphotericin B and ketoconazole and the neuroleptic trifluoperazine. It was clear that there are major differences between the two amebas in their susceptibility to some of the drugs. The drugs with the minimal inhibitory concentration (MIC) values could be considered alone or in combination as potential anti-amebic agents for the treatment of the diseases produced by these amebas.

Development of a psilocin immunoassay for serum and blood samples

After the immunisation of rabbits with a psilocin-specific immunogen, polyclonal antisera were obtained. With these antisera a competitive, heterogeneous radioimmunoassay for the detection of psilocin was developed. As tracer a derivative of psilocin was synthesised, which contained a tritiated CH(3) group. The antisera showed a specific reaction with psilocin. The cross-reactivity of structurally related endogenous substances like serotonin, tryptophan and tyrosine was below 0.01%. Also common drugs of abuse (Delta(9)-tetrahydrocannabinol, cocaine, morphine, amphetamine) showed negligible cross-reactivity (0.01-2%). Only tricyclic neuroleptics with a (dimethylamino)ethyl side-chain showed some cross-reactivity (20%). Spiked serum and blood samples were analysed with this new immunoassay and the results obtained were compared with the values measured with a validated GC-MS method.

Occurrence of CYP2D6 Gene Duplication in Hong Kong Chinese

The cytochrome P450 CYP2D6 enzyme debrisoquine 4-hydroxylase metabolizes many different type of drugs commonly used in psychopharmacotherapy, such as tricyclic antidepressants and neuroleptics (1). The CYP2D6 gene, which encodes for the CYP2D6 enzyme, is part of a cluster on chromosome 22 that includes two to three related pseudogenes (2). Starting at the 5′ end of the cluster, there are two nonfunctional pseudogenes termed CYP2D8P and CYP2D7AP (an additional pseudogene, CYP2D7BP , also can be found) followed by the active gene CYP2D6 . Several mutated alleles of the CYP2D6 gene have been identified (3) and associated with alterations or polymorphisms in the metabolism of debrisoquine and related drugs metabolized by the CYP2D6 enzyme. As a result, CYP2D6 enzymatic activity ranges from ultrafast to a complete absence; the corresponding phenotypes are called ultrarapid (UM), extensive, and poor (PM) metabolizer. Unequal distribution of the alleles among different populations gives rise to interracial metabolic differences in addition to interindividual variation (4). Individuals homozygous or heterozygous for deficient CYP2D6 alleles metabolize drugs at a low rate, increasing the risks of side effects and drug toxicity. On the other hand, individuals with duplication/multiplication of the active CYP2D6 gene metabolize drugs at ultrarapid rate, hence requiring more than average doses of drugs to reach therapeutic plasma concentrations (5). The mechanism behind the duplication involves mainly the active allelic variant CYP2D62 (6). The occurrence of gene duplication varies widely, from 29% in Ethiopians (7), to 20% in Saudi Arabians (8), to 1–7% in Caucasians (9)(10), to 1–2% in Orientals (11)(12)(13), although not many data are available for the latter. Establishing the prevalence of duplicated CYP2D6 active alleles may help prevent therapeutic failure in UM individuals treated with CYP2D6 enzyme-substrates at standard doses. We investigated the prevalence of the …

Inhibitory and lytic effects of phenothiazine derivatives and related tricyclic neuroleptic compounds, on Entamoeba histolytica HK9 and HM1 trophozoites.

It has been shown previously that tricyclic neuroleptics like clomipramine and chlorpromazine have lethal effects on Leishmania donovani and L. major, and other studies indicate that the phenothiazine inhibitors of trypanothione reductase are potential anti-trypanosomal and anti-leishmanial drugs. With this in mind and our original observation on the presence of trypanothione in Entamoeba histolytica HK9, we examined the possible inhibitory effects of various phenothiazine and tricyclic derivatives on this human parasite. We found that drugs like clomipramine (KD002), the most potent in vitro inhibitor of trypanothione reductase among 30 tricyclic compounds tested, at 25 microM after 24 h of culture under aerobic conditions, caused a substantial decrease in the number of E. histolytica HK9 trophozoites, from approx. 15 x 10(6) to 5.37 x 10(6) cells, and at 100 microM to 0.8 x 10(6) cells. A substantial inhibitory effect on cell proliferation could also be demonstrated with metronidazol (used clinically against amoebiasis). Under similar experimental conditions other tricyclic and phenothiazine derivatives (OFKs), designed originally to inhibit the trypanothione reductase of trypanosomatides, had an inhibitory effect of 16 to 95%. For comparison, similar results were obtained using clomipramine and a phenothiazine derivative (OFK006) with Trypanosoma cruzi and Crithidia luciliae, except that with the latter the inhibitory effect of clomipramine was less dramatic. Experiments comparing two E. histolytica strains showed that normal cell proliferation under anaerobiosis was higher in strain HK9 than in HM1, which is highly virulent, but that metronidazol and clomipramine were less effective against HM1. Two other drugs tested, diphenydramine (KD005) and a phenothiazine derivative (OFK008), also had significant but lower inhibitory effects on both strains. The inhibitory activity on cell proliferation and the lytic effects on this human parasite by the tricyclic compounds clomipramine, chlorpromazine and others, as well as by the phenothiazine derivatives, indicate that they can be considered potential anti-amoebic agents.

SSRIs for Delusional Depression

An earlier Italian study reported that the selective serotonin reuptake inhibitor (SSRI) fluvoxamine alone was as effective as combinations of tricyclic antidepressants and neuroleptics for the treatment of delusional depression (see JW for Psychiatry May 1996, p. 39, or Am J Psychiatry 1996; 153:414). Now, these same investigators have compared the efficacy of two SSRIs …

Managing selective serotonin reuptake inhibitor-drug interactions in clinical practice.

Combination drug therapy is common in psychiatry. It plays a role in the treatment of patients with multiple disorders, in the management of residual symptoms or resistant disease, and in the alleviation of unwanted effects of the primary drug. Coadministration of psychotropic drugs with medications for medical illnesses is becoming more common as well, because as many as half the patients with major depression require long term treatment, and because the number of patients who are elderly is increasing as the population ages. To safely manage multidrug regimens, the clinician must be knowledgeable about drug-drug interaction potential. Drug-drug interactions can produce a change in the pharmacological effect of a drug by altering activity at the site of action (a pharmacodynamic interaction), or by changing the plasma concentrations of a drug (a pharmacokinetic interaction), or both. Selective serotonin reuptake inhibitors (SSRIs) have the potential to impair the oxidative metabolism of several drugs, including tricyclic antidepressants and neuroleptics. However, the SSRIs highlight the maxim that overgeneralisation can be as detrimental to rational co-pharmacy as ignorance of interaction potential. The SSRIs differ in terms of which other drugs they affect, which patients are at risk, and to what extent the effect is clinically important. Clinicians must assess drug combinations on a case-by-case basis. Standard management practices of dose titration, monitoring plasma drug concentrations when the therapeutic index is narrow, and observing for adverse events minimise the clinical impact of potential drug-drug interactions.

Crystal and Molecular Structures of Tricyclic Neuroleptics

The X-ray crystal structures of three tricyclic neuroleptics have been completed and are reported herein. These include amitriptyline hydrochloride (I), chlorprothixene hydrochloride (II), and ethopropazine hydrochloride (III). The structures were compared with the structures of similar molecules with similar pharmacological activity. It was found that there is a great deal of flexibility in the structures of these molecules, which makes it difficult to determine the pharmacologically active conformations. Crystallographic data: (I) C20H24NCI, monoclinic space groupP21/a,a= 13.812(4) Å,b= 9.140(2) Å,c= 14.345(4) Å, β = 96.82(2)°,Z= 4, finalR= 0.059 for 1630 observed (l3σ(l)) reflections. (II) C18H20NSCI2. CHCI3, monoclinic space groupC2/c, a= 29.416(4) Å,b= 6.986(1) Å,c= 23.374(3) Å, β = 109.78(1)°,Z= 8, finalR= 0.046 for 1436 observed reflections. (III) C19H25N2SCI, monoclinic space groupP21/c, a = 8.849(1) Å,b= 14.475(2) Å,c= 14.832(1) Å, β = 98.72(1)°,Z= 4, finalR= 0.039 for 2583 observed reflections.

Antileishmanial actions of tricyclic neuroleptics appear to lack structural specificity

There is continuing interest in the antimicrobial effects of tricyclic neuroleptics and antidepressants, particularly against trypanosomatid protozoa, but few studies have attempted to dissociate antiparasitic actions from effects on the central nervous system. In this report, we have measured the antileishmanial potency of a range of structural analogues in this drug group, and conclude that no one structural determinant is critical for activity. Instead, potency may be predicted from an overall determination of the lipophilic and steric components of the structure by a simple combination of two descriptive parameters, valence connectivity and an interactive term.

Psychopharmacology and Psychobiology of Ethnicity

Are there differences in the responses to medication among different ethnic groups? This book gives the state-of-the-art answer and discusses the increasingly complex issues in the pharmacokinetics and pharmacodynamics of medications in whites, African Americans, Asian Americans, Hispanic Americans, and American Indians. In an interesting and provocative way, the authors describe the multiple issues involved in the choice of psychotropic medication for patients of diverse ethnic backgrounds and also consider appropriate dosages for individual patients. The first of the book's three sections is an introduction and overview, which discusses both the basic issues in psychopharmacology and psychobiology as related to ethnicity and the interface between psychobiology and ethnicity. Nonbiological issues and cultural considerations also are discussed. Chapter 3 deals with important issues like compliance and placebo effects. The second section focuses on ethnicity and psychopharmacology. Different chapters cover tricyclic antidepressants, benzodiazepines, lithium, neuroleptics, and ethanol. For example, in chapter 4,

ChemInform Abstract: Tricyclic Neuroleptics: Synthesis of Metabolites of Isofloxythepin and Some Related Compounds.

AbstractThe metabolites (VII) and (IX) of the neuroleptic agent isofloxythepin (X) and some related compounds are prepared.

Tricyclic neuroleptics: Synthesis of metabolites of isofloxythepin and some related compounds

The isofloxythepin (I) metabolite IV was synthesized via the acids IX and XI and the esters X and XII. The enamine VIII was prepared from 3-fluoro-8-(2-propyl)dibenzo[b,f]thiepin-10(11H)-one by two methods and was reduced to I. Cloflumide (II) was obtained by reaction of 2,10-dichloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin with 3-(1-piperazinyl)propionamide and was oxidized to the sulfoxide XVI. The unsaturated analogue XVII of clopithepin (III) was prepared from 2-chlorodibenzo[b,f]thiepin-10(11H)-one by reaction with 2-bromoethanol in the presence of 4-toluenesulfonic acid in boiling benzene and by the following substitution reaction with 2-(1-piperazinyl)ethanol. An improved synthesis of 6-methyldibenzo[b,f]thiepin-10(11H)-one (XIX) was elaborated. The acid XXVII was synthesized and cyclized with polyphosphate ester. A mixture of compounds was formed from which the ketone XXXVI was isolated and processed by reaction with formamide and formic acid at 200 °C. One of the products was characterized as the formamide XXXIII and was reduced with lithium aluminium hydride to a basic product supposed to be XXXIV. A series of by-products was isolated and characterized. The enamine VIII (V⁄FB-17 156) was found to be a strong neuroleptic agent, similar to isofloxythepin (I). The enol ether XVII (V⁄FB-17 733) was characterized as a mild, practically noncataleptic neuroleptic agent.

Agranulocytosis and significant leucopenia with neuroleptic drugs: results from the AM�P program

In the Federal Republic of Germany adverse drug reactions (ADR) have been continuously assessed at the departments of Psychiatry of Berlin and Munich since May 1979. About 13,000 neuroleptic-treated inpatients were monitored until August 1988. Approximately 1100 patients were exposed to clozapine, 6800 to haloperidol and 6000 to perazine, the two most frequently used neuroleptic drugs. In this 9-year period seven cases of agranulocytosis were observed, all in women. One case occurred with clozapine in monotherapy, the other six with perazine, three times in monotherapy, once in combination with trimethoprim/sulfamethoxazole and in one case each in combination with tricyclic antidepressants. Significant leucopenia (less than or equal to 3000/mm3) was observed in an additional eight cases. On four occasions each butyrophenones (twice in combination with TCA) and tricyclic neuroleptics (once in combination with TMS) were involved. The number of exposed patients per drug is too small for calculation of statistically valid incidence rates, especially in view of the frequent polypharmacy. The course of agranulocytosis was benign in all seven cases and required no other treatment than drug withdrawal in three cases. The early detection by regular WBCs is supposed to be mainly responsible for this and is therefore recommended at weekly intervals. This measure of safety appears most important for all medium potency tricyclic neuroleptics. As to treatment of agranulocytosis, additional measures (antibiotics, intensive medical care) depend upon the severity of the clinical picture.

ChemInform Abstract: Fluorinated Tricyclic Neuroleptics with Prolonged Action: Derivatives and Analogues of 2‐(4‐(7‐Fluoro‐2‐isopropyl‐10,11‐dihydrodibenzo(b,f)thiepin‐11‐yl)piperazine‐1‐yl)ethanol.

AbstractThe intermediate (IV) in the synthesis of the title compound (V) and the title derivatives and analogues (IX) are prepared starting from the aniline (I) and the compounds (V), (X) and (XIII), respectively.

Fluorinated tricyclic neuroleptics with prolonged action: derivatives and analogues of 2-(4-(7-fluoro-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepin-11-yl)-piperazine-1-yl)ethanol

The preparation of 4-fluoro-2-nitrobenzonitrile (V), an intermediate in the synthesis of the title compound I, from 4-fluoro-2-nitroaniline via 5-fluoro-2-iodonitrobenzene (VII) was elaborated. Syntheses of 1,1,1,3,3,3-hexadeutero-2-propyl (XX) and 1,3,4-trideutero (XXVIII) analogues of compound I from hexadeuteroacetone, and pentadeuterobromobenzene, respectively, were carried out. Compound I was esterified with acetic anhydride, decanoic acid and 3,4,5-trimethoxybenzoyl chloride to give the esters II-IV. Acylation of compound XXX with acetyl chloride, 4-fluorophenoxyacetyl chloride and (4-fluorophenylthio)acetyl chloride and the following reduction of the amides with lithium aluminium hydride gave compounds XXXII, XXXIX and XL. Substitution reactions of 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepin with the corresponding N-monosubstituted piperazines resulted in compounds XXXIII-XXXV, XXXVII, XXXVIII, XLI and XLII. Alkylation of XXX with 2-(2-chloroethyl)-1,3-dioxolane afforded compound XXXVI. Pharmacological testing of the new compounds, derivatives and analogues of the neuroleptic agent isofloxythepin (I), for discoordinating and cataleptic activities, showed especially for compounds II, XXXIV and XXXVI very intensive and long-lasting effects. The decanoate III has properties of a depot neuroleptic agent.

Investigation of the binding of various tricyclic neuroleptics and antidepressants to alpha 1-acid glycoprotein.

Recent studies have shown that the interaction of various tricyclic neuroleptics and antidepressants with isolated alpha 1-acid glycoprotein occurs at one common binding site and with relatively high association constants. The aim of the present study was to find differences in the binding of some phenothiazines, thioxanthenes, and several other drugs reported to bind alpha 1-AGP. The findings suggest that the affinity of the phenothiazines and thioxanthenes depends primarily on the existence of the tricyclic skeleton and is generally increased by the basic side chain. Substituents at position 3 of the phenothiazine nucleus influence the affinity in a variable way. The losses of radioactivity by non-specific absorptions to the dialysing chambers were considered for the calculation of the association constants. No correlation between association constants and the antipsychotic potency of neuroleptic drugs could be detected.