Structure-based discovery of nonhallucinogenic psychedelic analogs.

Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR ß-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.

Pharmacological profile of 2-bromoterguride at human dopamine D2, porcine serotonin 5-hydroxytryptamine 2A, and α2C-adrenergic receptors, and its antipsychotic-like effects in rats.

Dopaminergic, serotonergic, and adrenergic receptors are targets for therapeutic actions in schizophrenia. Dopamine D2 receptor partial agonists such as aripiprazole represent a treatment option for patients with this severe disorder. The ineffectiveness of terguride, another D2 receptor partial agonist, in treating schizophrenia was recently attributed to its considerably high intrinsic activity at D2 receptors. In this study, we used functional assays for recombinant D2 receptors and native 5-hydroxytryptamine 2A (5-HT2A), α2C-adrenergic, and histamine H1 receptors to compare the pharmacological properties of terguride and three of its halogenated derivatives (2-chloro-, 2-bromo-, 2-iodoterguride) with those of aripiprazole. Subsequently, we studied the antidopaminergic effects of 2-bromoterguride using amphetamine-induced locomotion (AIL). Its influence on spontaneous behavior was tested in the open field. Extrapyramidal side effect (EPS) liability was evaluated by catalepsy test. In a guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding assay, 2-chloro-, 2-bromo-, and 2-iodoterguride produced intrinsic activities at human D2short (hD2S) receptors that were half as high as the intrinsic activity for terguride; aripiprazole lacked agonist activity. 2-Bromoterguride and aripiprazole activated D2S receptor-mediated inhibition of cAMP accumulation to the same extent; intrinsic activity was half as high as that of terguride. All compounds tested behaved as antagonists at human D2long/Gαo (hD2L/Gαo) receptors. Compared with aripiprazole, terguride and its derivatives displayed higher affinity at porcine 5-HT2A receptors and α2C-adrenoceptors and lower affinity at H1 receptors. 2-Bromoterguride inhibited AIL and did not induce catalepsy in rats. Because of its in vitro and in vivo properties, 2-bromoterguride may be a strong candidate for the treatment of schizophrenia with a lower risk to induce EPS.

Antiserotonergic properties of terguride in blood vessels, platelets, and valvular interstitial cells.

Serotonin (5-hydroxytryptamine; 5-HT) is involved in heart valve tissue fibrosis, pulmonary arterial fibrosis, and pulmonary hypertension. We aimed at characterizing the antiserotonergic properties of the ergot alkaloid derivative terguride [1,1-diethyl-3-(6-methyl-8α-ergolinyl)urea] by using functional receptor assays and valvular interstitial cell culture. Terguride showed no vasoconstrictor effect in porcine coronary arteries (5-HT(2A) receptor bioassay) and no relaxant effect in porcine pulmonary arteries (5-HT(2B) receptor bioassay). Terguride behaved as a potent antagonist at 5-HT(2A) receptors (noncompetitive antagonist parameter pD'2 9.43) and 5-HT(2B) receptors (apparent pA2 8.87). Metabolites of terguride (N″-monodeethylterguride and 6-norterguride) lacked agonism at both sites. N″-monodeethylterguride and 6-norterguride were surmountable antagonists at 5-HT(2A) receptors (pA2 7.82 and 7.85, respectively) and 5-HT(2B) receptors (pA2 7.30 and 7.11, respectively). Kinetic studies on the effects of terguride in pulmonary arteries showed that the rate to reach drug-receptor equilibrium for terguride was fast. Washout experiments showed that terguride easily disappeared from the receptor biophase. Pretreatment with terguride inhibited 5-HT-induced amplification of ADP-stimulated human platelet aggregation (IC50 16 nM). In porcine valvular interstitial cells, 5-HT-induced activation of extracellular signal-regulated kinase (ERK) 1/2, an initiator of cellular proliferation and activity, was blocked by terguride as shown by Western blotting. In these cells, the stimulatory effect of 5-HT on [³H]proline incorporation (index of extracellular matrix collagen) was blocked by terguride. Because of the inhibition of both 5-HT(2A) and 5-HT(2B) receptors, platelet aggregation, and cellular proliferation and activity (ERK1/2 phosphorylation and collagen production) terguride may have therapeutic potential in the treatment of fibrotic disorders.

Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic.

Aripiprazole is the first clinically approved atypical antipsychotic agent having dopamine D2 receptor partial agonist activities. To evaluate aripiprazole's agonist and antagonist properties, we established a Chinese hamster ovary cell line expressing high and low densities of the long and short isoforms of human dopamine D2 receptors, then compared its properties with 7-{3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(1H)-quinolinone (OPC-4392), S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP), and terguride (other partial agonists) using forskolin-stimulated cAMP accumulation as an index. In cells expressing high receptor densities, all partial agonists predominantly behaved as agonists. However, in cells expressing low receptor densities, the partial agonists showed significantly lower maximal effects than dopamine. Aripiprazole showed the lowest intrinsic activities. In addition, all compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. Aripiprazole's low intrinsic activities may account for the clinical finding that, unlike the other partial agonists, it is substantially active against both positive and negative symptoms of schizophrenia.

Pergolide, terguride and N,N'-spacer-linked oligomers of both interact with 5-HT2A receptors of rat tail artery.

Pergolide, terguride and N,N'-spacer-linked oligomers of both have been tested for their ability to interact with 5 hydroxytryptamine(HT)2A receptors of rat tail artery. Pergolide was a potent partial agonist (pEC50 7.5, Emax 55 %) and antagonized 5-HT-induced contractions (pKp 7.2). Pergolide dimer 3 with a p-xylene spacer between the indole nitrogens (N-1) displayed somewhat lower agonist potency than pergolide (pEC50 7.0, Emax 55 %, pKp 6.6). The contractile responses to pergolide and dimer 3 were antagonized by the 5-HT2A receptor antagonist ketanserin (pA2 9.4, 9.1). In contrast to pergolide dimer 3, pergolide dimers 5 and 9 with an alkyl and an aralkyl spacer between the piperidine nitrogens (N-6) lacked agonism and displayed low affinity at 5-HT2A receptors (pA2 < 5.5). Terguride behaved as an insurmountable antagonist of 5-HT (pA2 8.4). Oligomers of terguride showed 5 to 50-fold lower affinity. It is concluded that pergolide and terguride show a high affinity for 5-HT2A receptors, but dimerization (oligomerization) of both drugs fails to increase affinity.

Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats.

RATIONALE: There is substantial evidence that lisuride can produce effects linked to 5-HT(1A) receptor occupancy. Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT(2A/2C) receptor activation in hallucinogenesis. These conclusions are surprising when one considers that the potent interaction of lisuride with 5-HT(1A) receptors has been demonstrated in several different laboratories and that activation of 5-HT(1A) and 5-HT(1B) receptors can modulate dopaminergically mediated responses. OBJECTIVE: The lack of full substitution of lisuride for lysergic acid diethylamide (LSD) in drug discrimination experiments and induction of a pronounced 5-HT syndrome by this compound at relatively low doses convinced us to execute two series of experiments that might explain the primary mechanism responsible for lisuride-mediated biological effects and its paradoxical classification as a dopamine agonist in the literature. RESULTS: In drug discrimination studies, lisuride fully mimicked the 5-HT(1A) agonist LY 293284, only partially substituted for LSD and DOI, and failed to substitute for (+)-amphetamine. Lisuride produced a significant dose-related increase in flat body posture, forepaw treading, and lower-lip retraction which reflect a modulation of behavior by action at central 5-HT(1A) receptors. Only pMPPI [4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride], a selective 5-HT(1A) antagonist, was effective in inhibiting all 5-HT syndrome behaviors produced by lisuride, whereas pMPPI was without effect on any behavior induced by LSD. Lisuride dose dependently decreased body temperature in rats with a potency similar to that of the selective 5-HT(1A) agonist LY 293284. The hypothermic effect of lisuride was prevented by pre-injection of pMPPI, but not by ketanserin or haloperidol. CONCLUSION: We have demonstrated that the behavioral effects of low doses of lisuride are clearly mediated by stimulation of 5-HT(1A) receptors.

Effects of dopamine on the in vivo binding of dopamine D2 receptor radioligands in rat striatum.

The effects of moderate changes in extracellular dopamine concentrations on the in vivo binding of specific dopaminergic D2 radioligands with different affinities and kinetics were investigated in rats. Either [125I]NCQ298 (Kd = 19 pM), or [25I]iodolisuride (Kd = 0.27 nM) or [3H]raclopride (Kd = 1.5 nM) were administered intravenously (IV) to animals 1 h after the intraperitoneal (IP) injection of either alpha-methyl-p-tyrosine (AMPT) (250 mg/kg) or nomifensine (15 mg/kg), or saline. The kinetics of radioactivity concentration in the striatum, cerebellum, and plasma were measured for up to 4 h after [125I]NCQ298 or [125I]iodolisuride injection and up to 1.5 h after [3H]raclopride injection. For each tracer, the striatum-to-cerebellum radioactivity concentration ratios (S/C) and the binding potential (BP), calculated as the association to dissociation binding rate constant ratios (k3/k4), were assessed and related to the changes in extracellular dopamine concentration induced by drug treatments. Results show that S/C and BP of [3H]raclopride were significantly diminished by pretreatment with nomifensine, a drug that increases extracellular dopamine concentration. Nomifensine pretreatment induced no changes in the in vivo binding indexes of the high affinity [125I]NCQ298 and a slight but not significant decrease of the binding indexes of 125I]iodolisuride. Treatment with AMPT, which induced a 40% reduction in dopamine concentration, did not change [125I]NCQ298 binding indexes but slightly increased those of [3H]raclopride and [125I]iodolisuride. In conclusion, the change of dopamine concentration induces modification of radiotracer kinetics. Thus, the combined use of tracers with high and low affinities could allow us to obtain information both on receptor density and neurotransmitter release in vivo. However, as indicated by the [3H]raclopride study with AMPT, small changes in the concentration of intrasynaptic dopamine cannot be easily detected.

Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors.

Evidence from studies with phenylisopropylamine hallucinogens indicates that the 5HT2A receptor is the likely target for the initiation of events leading to hallucinogenic activity associated with LSD and related drugs. Recently, lisuride (a purported non-hallucinogenic congener of LSD) was reported to be a potent antagonist at the 5HT2C receptor and an agonist at the 5HT2A receptor. LSD exhibited agonist activity at both receptors. These data were interpreted as indicating that the 5HT2C receptor might be the initiating site of action for hallucinogens. To test this hypothesis, recombinant cells expressing 5HT2A and 5HT2C receptors were used to determine the actions of LSD and lisuride. LSD and lisuride were potent partial agonists at 5HT2A receptors with EC50 values of 7.2 nM and 17 nM, respectively. Also, LSD and lisuride were partial agonists at 5HT2C receptors with EC50 values of 27 nM and 94 nM, respectively. We conclude that lisuride and LSD have similar actions at 5HT2A and 5HT2C receptors in recombinant cells. As agonist activity at brain 5HT2A receptors has been associated with hallucinogenic activity, these results indicate that lisuride may possess hallucinogenic activity, although the psychopharmacological effects of lisuride appear to be different from the hallucinogenic effects of LSD.

Radiochemical synthesis of [123I]2-iodo-lisuride for dopamine D2-receptor studies.

By variation of reaction parameters iodination of 3-(9,10-didehydro-6-methyl-8 alpha-ergolinyl)-1,1-diethylurea (lisuride) was performed with the radiohalogen [123I]iodine (t1/2 = 13.3 h). For comparative experiments and stability studies the beta(-)-emitting radioisotope [131I]iodine (t1/2 = 8.04 d) was also used. Reaction occurs at the activated position 2 of the molecule, thus leading to [123I]3-(9,10-didehydro-2-iodo-6-methyl-8 alpha-ergolinyl)-1,1-diethylurea ([123I]2-iodo-lisuride, [123I]ILIS) or the analogous [131I]iodine-labeled compound, respectively. Electrophilic radioactive species were generated by oxidation of no-carrier-added (n.c.a.) iodide with IODOGEN (1,3,4,6-tetrachloro-3 alpha,6 alpha-diphenylglycouril) fixed on the glass wall of the reaction vial prior to iodination. After optimization of reaction parameters [123I]2-iodo-lisuride after HPLC-purification was obtained with radiochemical yields of 70 +/- 5% and a radiochemical purity of > 97%. In n.c.a. syntheses, specific activities of the product were in the range between 4440 and 7400 GBq/mumol (120-200 Ci/mumol) corresponding to 50-85% of the theoretical value.

Characterisation of recombinant serotonin 5-HT1A receptors expressed in Chinese hamster ovary cells: the agonist [3H]lisuride labels free receptor and receptor coupled to G protein.

Serotonin 5-HT1A receptors expressed stably in recombinant Chinese hamster ovary cells have been studied using radioligand binding with the radiolabelled agonist [3H]lisuride. Competition studies with a range of antagonists versus [3H]lisuride confirmed that all of the specific [3H]lisuride binding was to 5-HT1A receptors on the cells. Competition studies with the antagonist spiperone and several agonists gave data that fitted best to two-binding-site models. The affinities of these competing ligands at the two classes of sites were generally in agreement with their corresponding affinities determined in previous work with either 8-[3H]hydroxydipropylaminotetralin ([3H]8-OH-DPAT; labels receptor coupled to G protein) or [3H]spiperone (labels free receptor). Saturation analyses with [3H]lisuride showed that this radioligand labels a single class of binding sites, but the level of radioligand binding was approximately twice that seen when either [3H]8-OH-DPAT or [3H]spiperone was used. [3H]Lisuride binding was partially inhibited by addition of guanine nucleotides, and the extent of inhibition decreased as the [3H]lisuride concentration was increased. This inhibition was due to the effect of guanine nucleotide to decrease slightly the affinity of [3H]lisuride for binding to the 5-HT1A receptors on the cells. It is concluded that [3H]lisuride can label both the free receptor and the receptor coupled to G proteins but with slightly different affinities and that these two states of the receptor exist in roughly equal amounts in the cells. Agonists generally have a higher affinity for the receptor coupled to G protein, whereas antagonists, with the exception of spiperone (which has a higher affinity for the free receptor), have roughly equal affinities for the free receptor and the receptor coupled to G proteins.

Stable expression of human cytochrome P450 3A4 in V79 cells and its application for metabolic profiling of ergot derivatives.

Expression of human cytochrome (CYP) in heterologous cells is a means of specifically studying the role of these enzymes in drug metabolism. The complete cDNA encoding CYP3A4 (PCN1) was inserted into an expression vector containing the strong myeloproliferative sarcoma virus promoter in combination with the enhancer of the cytomegalovirus and stably expressed in V79 Chinese hamster cells. The presence of genomically integrated CYP3A4 cDNA cell clones was confirmed by polymerase chain reaction analysis. Transcription was detected by reverse transcribed polymerase chain reaction analysis. Functional expression could be demonstrated by conversion of testosterone to the specific 6beta-hydroxylated product. In recombinant V79 cells expressing CYP3A4 about 6% of the substrate was converted to 6beta-hydroxytestosterone. The metabolism of two dopaminergic ergot derivatives was investigated in live recombinant V79 cells. Both lisuride and terguride were monodeethylated.

[Brain SPECT with 123I-lisuride in patients with Parkinson's disease and controls]. / Hirn-SPECT mit 123I-Lisurid bei Morbus-Parkinson-Patienten und Kontrollen.

The goal was to visualize cerebral dopamine-D2 receptors in 6 patients with Parkinson's disease and in 3 healthy controls using iodine-123-Lisuride-SPECT. In addition, we performed receptor-replacement studies using 123I-Lisuride and cold Lisuride as competitive ligands. The highest uptake of 123I-Lisuride was observed in the striatum, a region with known high dopamine receptor density. In two patients premedication with cold Lisuride displaced 123I-Lisuride from the dopamine receptor. 123I-Lisuride is valuable as a radiotracer in cerebral dopamine-D2 receptor scintigraphy. Whether or not it is possible to determine dynamic changes of dopamine receptor density or function by receptor replacement studies needs further evaluation in larger patient populations.

Terguride as a new anti-hyperprolactinemic agent: characterization in rats and dogs in comparison with bromocriptine.

Terguride, a derivative of the ergot alkaloid, was characterized as a new anti-hyperprolactinemic agent in rats and dogs in comparison with bromocriptine. Terguride was found to bind selectively to the pituitary dopamine D2-receptors with a high affinity (Kd = 0.39 nM). In reserpinized rats, terguride at 0.03 mg/kg, p.o. significantly reduced the serum prolactin (PRL) level. The PRL lowering effect and the effective dose were longer lasting and about 30 times lower than those of bromocriptine, respectively. In rats bearing estrogen-induced pituitary prolactinoma, chronic terguride induced shrinkage of the prolactinoma as well as reduction of the high serum PRL level. In lactating rats, terguride (1.0 mg/kg, s.c.) reduced milk production in the mammary gland, whereas bromocriptine showed no significant effect up to 10 mg/kg, s.c. Terguride (10 mg/kg, p.o.) did not induce any stereotypy and hypermotility in reserpinized rats, while bromocriptine induced both stereotypy and hypermotility significantly at 10 mg/kg, p.o. In dogs, terguride, like bromocriptine, reduced the serum PRL level, but did not affect the serum levels of growth hormone and luteinizing hormone. In dogs, bromocriptine induced both emesis and PRL-lowering at almost the same dose, whereas emesis-inducing doses of terguride were about 100 times higher than the PRL-lowering dose. These results suggest that terguride as a dopamine D2-agonist is a potent inhibitor of PRL secretion with less neurotropic side effects compared to bromocriptine, and thus a useful drug for the treatment of galactorrhea and hyperprolactinemia including prolactinoma.

[Effects of terguride, an ergot alkaloid derivative, on the central nervous system: biochemical and behavioral studies].

Effects of terguride, a 9,10-dihydrogenated derivative of lisuride, on the central nervous system were investigated in rodents in comparison with those of lisuride. In vitro binding studies in rat brains showed that terguride, similar to lisuride, had a high affinity for D2-, 5-HT1A-, 5-HT2-, alpha 1- and alpha 2-receptors. Terguride, as does lisuride, induced hypomotility and yawning at low doses in rats, suggesting its presynaptic D2-agonist action. Terguride, unlike the postsynaptic D2-agonist lisuride, induced neither hypermotility nor stereotypy in rats and guinea pigs, but suppressed the hypermotility and stereotypy induced by apomorphine. Terguride suppressed haloperidol-induced catalepsy in rats and induced contralateral rotations in unilaterally 6-OHDA-lesioned rats, as does lisuride. These effects may be due to the postsynaptic D2 partial agonist action. Terguride, unlike lisuride, neither induced the serotonin syndrome nor generalized to the discriminative stimuli of the 5-HT1A- agonist 8-OH-DPAT in rats. Terguride did not induce head twitch in mice. Terguride blocked noradrenaline-induced lethality and clonidine-induced hypothermia at high doses in mice. Repeated administration of terguride did not affect the behavioral actions in rats. Thus, the effects of terguride on the central nervous system seems to be produced by mediation of the agonist and partial agonist actions at presynaptic and postsynaptic D2- receptors, respectively.

6-[18F]fluoro-L-dopa uptake and [76Br]bromolisuride binding in the excitotoxically lesioned caudate-putamen of nonhuman primates studied using positron emission tomography.

The functional status of the dopaminergic system following striatal excitotoxic lesions was studied in living baboons by positron emission tomography (PET) using 6-[18F]fluoro-L-dopa as specific tracer for the presynaptic dopaminergic terminals and [76Br]bromolisuride as selective dopamine D2-receptor marker. The glutamate receptor agonist ibotenic acid (IA) was injected into the right caudate-putamen of six baboons to induce a neuropathological and behavioral model of Huntington's disease (HD). In vivo PET studies performed 3 to 6 months after the IA injections showed that subtotal excitotoxic lesions of the CP were accompanied by changes in the kinetic of [76Br]bromolisuride binding indicating a dose-dependent reduction in binding sites in the lesioned striatum of all IA-injected animals. In the most severely lesioned animals, there was also a decrease in the uptake of the nigrostriatal dopaminergic marker. The loss of D2-receptors and decrease in striatal dopamine uptake are consistent with clinical and postmortem findings in HD. In addition, the decrease in 6-[18F]fluoro-L-dopa uptake confirms previous studies performed in a rat model of HD suggesting a continuous decline of nigral dopamine cell function following destruction of their intrinsic striatal target neurons. The results of our experience to date in PET studies of 6-[18F]fluoro-L-dopa and [76Br]bromolisuride binding in IA-lesioned primates indicate that PET can identify effects of cell loss on markers of pre- and postsynaptic function in the striatum of living subjects.

Kinetic analysis of central [76Br]bromolisuride binding to dopamine D2 receptors studied by PET.

The in vivo kinetic analysis of dopamine D2 receptors was obtained in baboon brain using positron emission tomography (PET) and [76Br]bromolisuride [( 76Br]BLIS) as radioligand. An injection of a trace amount of [76Br]BLIS was followed 3 h later by an injection of a mixture of [76Br]BLIS and BLIS in the same syringe (coinjection experiment). A third injection performed at 6 h was either an excess of unlabeled ligand (displacement experiment) or a second coinjection. This protocol allowed us to evaluate in the striatum of each animal and after a single experiment the quantity of available receptors (B'max) and the kinetic parameters including the association and dissociation rate constants (k + 1VR and k-1, respectively, where VR is the volume of reaction). The cerebellum data were fitted using a model without specific binding. All the parameters were estimated using nonlinear mathematical models of the ligand-receptor interactions including or not including nonspecific binding. The plasma time-concentration curve was used as an input function after correction for the metabolites. An estimate of standard errors was obtained for each PET study and for each identified parameter using the covariance matrix. The average values of B'max and KdVR were 73 +/- 11 pmol/ml tissue and 1.9 +/- 0.9 pmol/ml, respectively. The nonspecific binding was identifiable in the experiment where the last injection corresponded to a second coinjection. We found that approximately 6% of the striatal binding was nonspecific after a tracer injection of [76Br]BLIS. The nonspecific binding appeared to be reversible in the striatum but irreversible in the cerebellum.

Pharmacokinetics of 3H-terguride in elderly volunteers.

Blood and plasma levels and excretion of labeled compounds and of the unchanged drug were measured after i.v. injection of 54 micrograms and p.o. administration of 540 micrograms of the ergoline derivative, terguride (CAS 37686-84-3), labeled with tritium, in 6 elderly male volunteers. Following i.v. injection plasma levels of terguride declined with a half-life of 0.5 h and those of radiolabeled compounds with half-lives of 0.5 h, 7 h and 19 h. The total clearance was 17 ml/min/kg and the volume of distribution was 0.7 l/kg. After p.o. administration terguride was rapidly and completely absorbed. The bioavailability was around 20%. Elimination of labeled compounds was complete within 7 days and proceeded mainly via the urine. Computer simulation of plasma levels after 4-times-a-day multiple administrations indicated slight accumulation of metabolites (factor 3) and no accumulation of terguride (factor 1).

Binding characteristics of the dopamine agonist/antagonist [3H]terguride (transdihydrolisuride) in the rat striatum.

The binding properties of [3H]terguride were studied in various regions of the rat brain. The highest density of [3H]terguride binding sites was found in the striatum and tuberculum olfactorium. In the striatum, the binding was saturable, stereoselective and of a high affinity. There was a good correlation between the inhibition of [3H]terguride and [3H]spiperone bindings by various dopaminergic agents. Drugs with affinity to another type of receptors did not displace [3H]terguride binding in the striatum; only SCH 23390 was effective. The experiments indicate a certain affinity of the ligand to D-1 receptors. Nevertheless, [3H]terguride appears to have an affinity to D-2 receptors in the striatum and, thanks to its dopamine agonistic/antagonistic profile, would be useful in the further study of dopamine receptors.