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The dopamine (DA) D 3 receptor antagonist PD 58491 (3-[4-[1-[4-[2-[4- (3-diethylaminopropoxy) phenyl]-benzoimidazol-1-yl-butyl]-I H-benzoimidazol-2-yl]-phenoxy]propyl]diethylamine) bound with high affinity and selectivity to recombinant human DA D 3 versus D 2L and D 4.2 receptors transfected into Chinese hamster ovary cells: K i values of 19.5 n M versus 2,362 and >3,000 nM, respectively. In contrast, the putative DA D 3 receptor antagonist (+)-AJ76 displayed low affinity and selectivity for D 3 versus D 2L and D 4,2 receptors (91 nM vs. 253 and 193 nM, respectively). In vitro, PD 58491 (1 nM-I M) exhibited D 3 receptor antagonist activity, reversing the quinpirole (10 nM)-induced stimulation of [ 3 H]thymidine uptake in D 3 CHOpro-5 cells, but did not have any significant intrinsic activity by itself in this assay. PD 58491 did not decrease the y-butyrolactone-induced increase in DA synthesis (L-3,4-dihydroxyphenylalanine accumulation) in rat striatum, indicating that the compound possessed no in vivo DA D 2 /D 3 receptor agonist action at DA autoreceptors. PD 58491 (3-30 mg/kg, i.p.) generally did not alter DA or serotonin synthesis in either the striatum or mesolimbic region of rat brain. The D 3 -preferring agonist PD 128907 decreased DA synthesis in striatum and mesolimbic regions, and this effect was attenuated by pretreatment with PD 58491. These findings support the hypothesis that DA D 3 autoreceptors may in part modulate the synthesis and release of DA in striatum and mesolimbic regions.

152255 ( E -1, 1′-(2-butene-1,4-diyl)bis [2-[4-[3-(1-piperidinyl)propoxy]-phenyl]-1H-benzimidazole]) exhibited high affinity ( K i = 12.7 nM) for human dopamine (DA) D 3 receptors expressed in CHO K1 cells but not for DA D 2L receptors ( K i = 565 nM), DA D 4.2 or DA D 1 receptors ( K i > 3 μ M) and a number of other neurotransmitter receptors. Affinity for human muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo. Antagonist activity at DA D 3 receptors was demonstrated by blockade of quinpirole-stimulated [ 3 H]-thymidine uptake in D 3 transfected cells, an effect that was 28-fold more potent than in D 2 -transfected cells. Unlike classical DA D 2 antagonists, PD 152255 did not increase rat brain DA synthesis and it increased locomotion in habituated rats. However, like antipsychotics, PD 152255 reduced locomotor activity in mice and reduced spontaneous and amphetamine-stimulated locomotion in nonhabituated rats. These results demonstrate that PD 152255 is a DA D 3 antagonist that may have antipsychotic activity.

The discovery of a series of novel (aryloxy)alkylamines with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. A number of compounds demonstrated subnanomolar Ki values for binding to the D4 receptor, with several 100-fold selectivities toward the D2 and D3 receptors. Several compounds with combined D3/D4 receptor binding selectivity were also identified. A limited structure-activity relationship study of this chemical series is discussed. In a mitogenesis functional assay, the effect of the test compounds on cellular uptake of [3H]thymidine in D4-transfected CHO 10,001 cells was measured and compared to the response of the full dopamine agonist quinpirole. The activity of the compounds varied from full antagonist to weak partial agonist activity (intrinsic activity of 0-19% in comparison to quinpirole).

The human dopamine D4 receptor (D4R) has received considerable attention because of its high affinity for the atypical antipsychotic clozapine and the unusually polymorphic nature of its gene. To clarify the in vivo role of the D4R, we produced and analyzed mutant mice ( D4R −/− ) lacking this protein. Although less active in open field tests, D4R −/− mice outperformed wild-type mice on the rotarod and displayed locomotor supersensitivity to ethanol, cocaine, and methamphetamine. Biochemical analyses revealed that dopamine synthesis and its conversion to DOPAC were elevated in the dorsal striatum from D4R −/− mice. Based on these findings, we propose that the D4R modulates normal, coordinated and drug-stimulated motor behaviors as well as the activity of nigrostriatal dopamine neurons.

The discovery of a series of chromeno[3,4-c]pyridin-5-ones with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. Several compounds demonstrated single digit nanomolar Ki values for binding to the D4 receptor with several hundred-fold selectivities toward the D2 and D3 receptors. A limited SAR study of this series is discussed. In a mitogenesis assay measuring [3H]thymidine uptake, the target compounds showed antagonist to weak partial agonist activity at the D4 receptor, with intrinsic activities ranging from 0 to 35%. Compound 6, 3-benzyl-8-methyl-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, increased DOPA (L-3,4-dihydroxyphenylalanine) synthesis 84% in the hippocampus and 10% in the striatum of rat brain when dosed orally at 10 mg/kg.

High volume screening identified 3-(4-benzylpiperidinyl)-1-naphthoxy-2-propanol as a selective dopamine D4 receptor ligand. A systematic structure-activity study revealed that the benzyl group could be replaced with phenoxy and the naphthalene with phenyl to improve potency almost tenfold. The (R) enantiomer of this compound had a D4 affinity of 2 nM and was over 100-fold weaker at dopamine D2 and D3 receptors.

The pharmacology of PD 144418 (1-propyl-5-(3-p-tolyl-isoxazol-5-yl)-1,2,3,6-tetrahydropyridine) was characterized using neurochemical, biochemical and behavioral techniques. For sigma (σ1 and σ2, respectively) sites, PD 144418 affinities were determined using whole guinea pig brain membranes with [3H](+)-pentazocine and neuroblastoma × glioma cell membranes using [3H]1,3-di-o-tolylguanidine (DTG) in the presence of 200 nM (+)-pentazocine. PD 144418 exhibited an affinity for σ1 of 0.08 nM (Ki) versus a Ki of 1377 nM for σ2 site. Additional receptor binding studies indicated that PD 144418 lacked affinity for dopaminergic, adrenergic, muscarinic and a variety of other receptors. In vitro studies indicated that PD 144418 reversed the N-methyl- d -aspartate (NMDA)-induced increase in cyclic GMP (cGMP) in rat cerebellar slices without affecting the basal levels, suggesting that σ1 sites may be important in the regulation of glutamine-induced actions. PD 144418 potentiated the decrease in 5-hydroxytryptophan caused by haloperidol in the mesolimbic region, but by itself had no effect in 5-hydroxytrypamine (5-HT) and dopamine (DA) synthesis. Behaviorally, similar to other σ ligands, PD 144418 antagonized mescaline-induced scratching at doses that did not alter spontaneous motor activity. This action is suggestive of potential antipsychotic property. It exhibited no anxiolytic and antidepressant properties in the models used. These results show that PD 144418 is a very selective σ1 agent, devoid of any significant affinity for other receptors and that σ1 site may modulate actions in the CNS. © 1997 Elsevier Science Ltd. All rights reserved.

A series of 4-bromo-1-methoxy-N-[2-(4-aryl-1-piperazinyl)ethyl]-2-naphthalenecarboxamide dopamine (DA) D 3 receptor agonists has been identified. These compounds were found to be selective for DA D 3 over D 2 receptors and were shown to be partial to full agonists as measured by stimulation of mitogenesis in D 3 -transfected CHO p-5 cells.

A novel series of dimeric 2-[4-(3-aminopropoxy)phenyl]benzimidazole dopamine (DA) D3 receptor antagonists has been discovered. Most of the dimeric structure is needed for DA binding activity; however, a second basic nitrogen atom is not required. A representative compound had no effects on DA synthesis in rat brain but inhibited spontaneous locomotor activity in mice and stimulated locomotor activity in habituated rats.

The pyridine analogs of 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT), 4-6, were synthesized, and their biological activity was compared to that of 5-OH-DPAT. Compounds 4 and 6 exhibited activity similar to 5-OH-DPAT in dopamine (DA) D2 and D3 receptor binding and in autoreceptor activation as measured by their ability to reverse the gamma-butyrolactone-induced increase in rat DA synthesis. Behaviorally, 4 and 6 decreased locomotor activity (LMA) in rats (sc) at low doses but did not increase LMA to the same extent as 5-OH-DPAT at higher doses, indicating that 4 and 6 may be more selective for the DA autoreceptor. While 4 was less active orally in rats, 6 appeared to retain most of its behavioral potency. Analog 5 showed little activity in vivo or in vitro.

In in vitro studies, SR 48692, a nonpeptide neurotensin receptor antagonist, inhibited the binding of [3H] or [125I]neurotensin to membrane preparations from 10-day-old mouse brains and from HT-29 cells with Ki values of 3.9 and 8.6 nM, respectively. SR 48692 also antagonized the neurotensin-induced mobilization of intracellular calcium in HT-29 cells, in agreement with previous findings. In rat cerebellar slices SR 48692 blocked the increase in cyclic GMP levels evoked by neurotensin in a dose-dependent manner. In vivo, SR 48692 antagonized the increase in rat brain mesolimbic dopamine turnover induced by the systemically active neurotensin peptide, EI [(N-Me)Arg-Lys-Pro-Trp-tert-Leu-Leu]. No effects on dopamine turnover of either EI or SR 48692 were observed in the striatum. SR 48692 did not antagonize the EI-induced decreases in mouse body temperature and spontaneous locomotor activity (LMA) or the decreases in LMA induced by ICV-administered neurotensin. Although other explanations are possible, these findings support the hypothesis that a subtype of the NT receptor may mediate the locomotor and hypothermic actions of this peptide and that it is different from the NT receptor that is involved in dopamine turnover.

4-Aryltetrahydropyridines were prepared and evaluated in dopamine (DA) D2 and σ binding assays. Introduction of substitutents into the 4 position of the aryl group on the tetrahydropyridine was found to both greatly decrease the affinity for the DA D2 receptor and increase the affinity for the brain σ binding sites.

The synthesis and resolution of 4,5,6,7-tetrahydro-6-[4-(2-pyridinyl)-1-piperazinyl]-2-benzothiazolamine (7), a centrally active dopamine (DA) agonist, are described. Unlike the structurally related 2-aminotetralins, both enantiomers of this compound possess comparable dopaminergic efficacy.

The present studies evaluated previous suggestions that haloperidol-sensitive sigma binding sites are involved in the modulation of dopamine (DA) neuronal activity and in the induction of the dystonic effects of antipsychotic drugs. These issues were addressed by evaluating the effects of compounds that have differing affinities for sigma binding sites, on the firing activity of DA neurons in the substantia nigra in chloral hydrate-anesthetized rats and on the ability to induce extrapyramidal motor dysfunction in squirrel monkeys sensitized to the dystonic effects of haloperidol. The agents studied included haloperidol, DTG (1,3-di-o-tolylguanidine), (+)-pentazocine, (+)-SKF 10,047, BMY 14802, 8-OH-DPAT and sulpiride. There was no relationship between affinity for sigma binding sites and the ability to either alter DA neuronal activity or to induce extrapyramidal motor dysfunction.

A series of rigid tricyclic analogues of the dopamine (DA) agonist PD 118440 [4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine] was synthesized and evaluated for dopaminergic activity and DA autoreceptor selectivity. (R)-(+)-6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin+ ++-2-amine [+)-6) was identified as the most selective DA autoreceptor agonist from this group of compounds. It inhibited spontaneous locomotor activity (LMA) in rodents, reversed the gamma-butyrolactone (GBL) induced accumulation of rat striatal DOPA and inhibited brain DA neuronal firing, all suggestive of direct DA autoreceptor agonist activity. However, (+)-6 is not completely free of postsynaptic DA activity, as evidenced by its stimulation of LMA in rats at high doses and its ability to produce stereotypy. On the other hand, (-)-6 appears to be a weak partial DA agonist with some effects on brain DA synthesis only at high doses. Like other DA autoreceptor agonists and DA antagonists, (+)-6 inhibited Sidman conditioned avoidance in squirrel monkeys, a test predictive of clinical antipsychotic activity. However, unlike classical antipsychotics, (+)-6 did not induce dystonias in haloperidol-sensitized squirrel monkeys, suggesting a minimal propensity toward extrapyramidal side effects (EPS).

The synthesis and resolution of 4,5,6,7-tetrahydro-6-[4-(2-pyridinyl)-1-piperazinyl]-2-benzothiazolamine (7), a centrally active dopamine (DA) agonist, are described. Unlike the structurally related 2-aminotetralins, both enantiomers of this compound possess comparable dopaminergic efficacy.

The enantiomers of the dopamine (DA) agonist PD 128483 (1) have been synthesized and characterized biochemically (D1, D2 receptor binding, effects on rat brain DA synthesis), electrophysiologically (inhibition of DA neuron firing) and behaviorally (effects on rat exploratory locomotor activity). While R-(+)−1 is a potent D2 agonist that stimulates both pre- and postsynaptic DA receptors, S-(−)−1 is a weak partial DA agonist able to stimulate only the more sensitive presynaptic DA receptors (DA autoreceptors).

The design, synthesis, and pharmacological properties of a novel type of 4-(1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamine with dopaminergic properties are described. In particular, 4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine (4c, PD 118440) and its allyl analogue (4i, PD 120697) have been identified as orally active dopamine (DA) agonists with pronounced central nervous system effects in tests that include [3H]-haloperidol and [3H]-N-propylnorapomorphine binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. The DA autoreceptor selectivity of these heterocyclic analogues of 3-(1-propyl-3-piperidinyl)phenol (3-PPP) was also evaluated. In this series, DA agonist activity was found to be highly dependent on the size of the N-alkyl substituent, the saturation level of the six-membered ring, and the mode of attachment of the 2-aminothiazole ring.

The present study describes the synthesis and in vitro pharmacology of a novel series of dopaminergic agents in which the classical phenylethylamine pharmacophore is replaced by a thienylethylamine moiety. In general, the novel compounds showed a moderate affinity for the dopamine (DA) D-2 and D-3 receptors. When the thienylethylamine moiety is fixed in a rigid system, the affinity for the DA receptor is significantly increased. However, in the tricyclic hexahydrothianaphthoxazine structure, the affinity for the DA receptors is diminished.

After decades of research around dopamine agonists, we have found a promising compound in S-PD148903 that represents a new type of prodrug, which in the rat is bioactivated to the catecholamine S-5,6-diOH-DPAT, known to display mixed dopamine D-1/D-2 receptor agonist properties just like apomorphine. This prodrug has an enone structure which by an oxidative bioactivation mechanism is converted to the corresponding catechol and is delivered enantioselectively into the CNS. This novel concept has the potential to revolutionize the treatment of Parkinson's disease by competing with L-DOPA, the current treatment of choice.

Epinephrine (E), norepinephrine (NE), and dopamine (DA) belong to a class of compounds known as catecholamines. A number of physical and chemical properties of E and NE, together with analytical techniques used to measure these amines and their metabolites, are reviewed. E was originally isolated from bovine adrenal glands; however, E and related compounds are now synthesized commercially from the starting material, catechol. The biosynthesis, storage, release, and the termination of action of catecholamines by re-uptake into the presynaptic neuron that released the amine, plus mechanisms involved in regulating levels of amines in the nerve terminals, are reviewed. By virtue of functional and molecular biology studies, at least 15 subtypes of catecholamine receptors have been identified. In most cases, these physically distinct subtypes each have important second messengers and pharmacological consequences that are summarized. Catecholamines and related compounds exhibit a wide diversity of physiological functions, and thus are involved therapeutically in a wide range of uses both in the peripheral and central nervous system. Keywords: Epinephrine; Norepinephrine; Metabolism; Catecholamines; Regulations; Storage; Release; Metabolite; Receptors; Pharmacology; Second messengers; Molecular biology; Therapeutic uses; DOPA; Parkinson's disease; Vasoconstrictors

As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure-activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.

The discovery of a series of chromen-2-ones with selective affinity for the dopamine (DA) D4 receptor is described. Target compounds were tested for binding to cloned human DA D2L, D3, and D4.2 receptor subtypes expressed in Chinese hamster ovary K1 cells. Several compounds demonstrated high affinity (

PD 108635 (1) was identified as a potent dopamine D4 ligand and we wanted to replace the benzylic alcohol with a metabolically more stable moiety. Investigations led to the discovery of a series of isoindolinones having D4 affinity.

The anticonvulsant drug gabapentin has been shown recently to exhibit anxiolytic and analgesic actions in animals. Such actions have been postulated in part to reflect effects on biogenic amine neuronal activity. Therefore the effects of gabapentin on biogenic amine neuronal activity were assessed by measuring the synthesis of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in rat brain and on the release of [3H] NE from rat hippocampal slices both in the presence and absence of the depolarizing agent 3,4-diaminopyridine (DAP). Gabapentin (30 and 100 mg/kg, i.p.) did not alter the basal synthesis rates of NE and DA as assessed by the unchanged accumulation of L-dihydroxyphenylalanine (DOPA) in the NE-enriched hippocampus and cortex and in the DA-enriched striatum and mesolimbic areas. Gabapentin also did not alter 5-HT synthesis as determined by the unaltered accumulation of 5-hydroxytryptophan (5-HTP) in the same brain areas. DAP (2 mg/kg, i.p.) induced a modest but significant increase in DOPA accumulation in the hippocampal, mesolimbic and striatal regions. This DAP-induced increase in DOPA accumulation was antagonized significantly in the hippocampus and mesolimbic regions by gabapentin at 30 and 100 mg/kg and in striatum by 100 mg/kg; a 10 mg/kg dose was inactive. DAP increased selectively 5-HT synthesis in hippocampus and this effect was blocked by gabapentin. These findings indicate that the increased synthesis of biogenic amines induced by DAP is antagonized by gabapentin. In support of the in vivo studies, gabapentin was also shown to inhibit the DAP-evoked release of [3H]NE from hippocampal slices. Although the underlying mechanism for these effects is unclear, the present findings nevertheless demonstrate that gabapentin has inhibitory effects on stimulated NE, DA and 5-HT neurons that may be involved in explaining in part the CNS effects of this drug.

A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with dopaminergic activity is described. The structure-activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and inhibition of locomotor activity (LMA) in rodents. The basic amine, alkyne chain length, and aryl groups were varied. Compounds having a 4-phenyl-1,2,3,6-tetrahydropyridine and an aryl group with hydrogen-bonding substituents separated by a butynyl chain were found to have the most potent dopaminergic activity. Several compounds that were found to have exceptional in vivo activity in LMA inhibition in rodents were evaluated for additional pharmacological activity including binding affinities for other DA receptor subtypes as well as effects on brain DA synthesis, DA neuronal firing, and conditioned avoidance responding in squirrel monkeys.

PD 128907 [4a R, 10 b R-(+)-trans-3, 4, 4a, 10 b-tetrahydro-4-n-propyl2 H,5H-[1]benzop-yrano[4,3-b] 1,4-oxazin-9-ol.], a selective dopamine (DA) D3 receptor agonist ligand exhibits about a 1000-fold selectivity for human D3 receptors (K-i, 1 nM) versus human D-2 receptors (K-i, 1183 nM) and a 10000-fold selectivity versus human D-4 receptors (K-i, 7000 nM) using [H-3]spiperone as the radioligand in CHO-K1-cells. Studies with [H-3]PD 128907, showed saturable, high affinity binding to human D-4 receptors expressed in CHO-K1 cells (CHO-K1-D-3) with an equilibrium dissociation constant (K-d) of 0.99 nM and a binding density (B-max) of 475 fmol/mg protein. Under the same conditions, there was no significant specific binding in CHO-K1-cells expressing human D-2 receptors (CHO-K1-D-2). The rank order of potency for inhibition of [H-3]PD 128907 binding with reference DA agents was consistent with reported values for D-3 receptors. These results indicate that [H-3]PD 128907 is a new, highly selective D-3 receptor ligand with high specific activity, high specific binding and low non-specific binding and therefore should be useful for further characterizing the DAD(3) receptors.

The enantiomers of reduced haloperidol (3a), azaperol (3b), and the related compound BMY-14802 (3c) were prepared in high optical purity. The affinity of these compounds for dopamine D2 and D3 receptors, and sigma S1 and S2 sites was determined in vitro. Both enantiomers of 3a display greatly decreased affinity for D2 and D3 receptors compared to haloperidol, although they still possess affinities in the 100-200-nM range. Both enantiomers of 3a possess potent and equal affinity for S1 sites (Ki: 1-2 nM), only slightly weaker than haloperidol (Ki: 0.33 nM). At S2 sites, (R)-(+)-3a displays similar affinity to haloperidol (Ki: 31 and 26 nM, respectively), while (S)-(-)-3a is slight more potent (Ki: 8.2 nM). The stereoselectivity profile of the enantiomers of 3b at D2 and D3 receptors is quite similar to that of 3a, (S)-(-)-3b being about 4 times more potent than its enantiomer at both receptors. (R)-(+)-3b binds preferentially to sigma S1 over S2 sites, while (S)-(-)-3b displays the opposite selectivity profile. Both enantiomers of 3c possess very weak affinity for D2 and D3 receptors. In a manner similar to the enantiomers of 3b, the affinity of (R)-(+)-3c is greater for S1 than S2 sites, while (S)-(-)-3c displays the opposite selectivity profile. Following parenteral administration of both enantiomers of 3a, dopamine synthesis and turnover in rat striatum, cortex, and mesolimbic areas were increased, in a manner similar to the effects produced by haloperidol itself. Additional studies will be required to assess with certainty whether the effects were due to the compounds themselves or simply were a consequence of the in vivo oxidation to haloperidol.

The R -(+)-isomer of 7-hydroxy-2-( N , N -di- n -propylamino)tetralin (7-OH-DPAT) bound with a more than 200-fold higher affinity to cloned human dopamine D 3 receptors ( K i = 0.57 nM) than to dopamine D 2 receptors; the corresponding S -(−)-enantiomer had considerably less affinity for both dopamine receptor subtypes, indicating that the known enantiomer selctivity of 7-OH-DPAT for the ‘classical’ dopamine D 2 receptor subtype extends to the recently discovered dopamine D 3 receptor subtype. In rats R -(+)-7-OH-DPAT dose dependently (10–1000 nmol/kg) decreased dopamine release and induced yawning, while sniffing behaviour occured at the highest dose tested (1000 nmol/kg). The possibility that the inhibition of dopamine release and the elicitation of yawning are mediated by dopamine D 3 receptors is considered.

The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]-4H-1-benzopyran-4-ones with dopaminergic activity are described. The nature of the arylpiperazine (AP) moiety determines the dopamine (DA) agonist/antagonist character of this series of compounds; when the aryl portion of the AP is unsubstituted the compounds appear to be DA autoreceptor agonists while substituted aryl groups seem to impart DA antagonist activity. A heterocyclic piperazine, 7-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy]-4H-1-benzopyran-4-one (31, PD 119819) has been identified as an extremely selective DA autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of spontaneous locomotor activity, inhibition of brain DA synthesis, inhibition of brain DA neuronal firing, stereotypy assessment, and reversal of 6-hydroxydopamine (6-OHDA) induced akinesia in rats. In addition, 31 possesses good oral activity in the Sidman avoidance test in squirrel monkeys, a predictor of clinical antipsychotic efficacy. In another primate model, 31 has been found to lack the liability for extrapyramidal side effects observed with currently available antipsychotic drugs.

The dopamine agonist profile of (+-)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol (16a) and its enantiomers (16b-c) was examined. Racemic 16a exhibited moderate affinity for the dopamine (DA) D2 receptor labeled with the DA antagonist ligand [3H]haloperidol and moderate in vivo activity; it attenuated gamma-butyrolactone-stimulated DA synthesis, decreased DA neuronal firing of substantia nigra DA neurons, and inhibited exploratory locomotor activity in rats, a profile consistent with a DA autoreceptor agonist mechanism of action. The (+)-enantiomer 16b possessed greater DA receptor affinity with the agonist ligand [3H]-N-propylnorapomorphine than with the antagonist ligand. In rats it potently inhibited DA synthesis and neuronal firing and also inhibited exploratory locomotion. The (-)-enantiomer, on the other hand, did not have significant activity in any of these tests. This profile indicates that like many other rigid DA agonists, the dopaminergic activity resides in one enantiomer, in this case the (+)-enantiomer 16b. On the basis of single-crystal X-ray analysis of a key intermediate, the absolute configuration of 16b was found to be 4aR, 10bR.

The effects of clofibrate (240 mg/kg p.o. once a day for 4 days) on norepinephrine (NE) and dopamine (DA) concentrations and turnover in both the periphery and the brain and on levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) and 5-HT turnover in brain of the rat were determined. Clofibrate did not alter endogenous NE in either brain, heart or mesenteric artery nor DA in brain. Clofibrate did not alter brain 5-HT but elevated 5-HIAA levels. No effect on catecholamine turnover in either the brain or heart was observed. Following inhibition of trvptophan hydroxylase with the inhibitor cypropvldopacetamide, clofibrate antagonized the subsequent decline of 5-HT levels. From this latter finding it was concluded that clofibrate decreased the turnover of brain 5-HT.

The present study was initiated to examine the effect of pramiracetam sulfate [N-[2-[bis(1-methylethyl)amino]ethyl]-2 oxo-1-pyrrolidineacetamide sulfate (1:1)] (PR), a new cognition-activator agent, on various neurochemical parameters in order to gain some insight into the mechanism of action of this agent. PR (100 mg/kg i.p.) did not alter the concentration of norepinephrine, dopamine (DA), serotonin (5-HT), 5-hydroxyindoleacetic, and homovanillic acid in various brain areas. The agent also did not alter d-methamphetamine-induced changes in monoamine metabolism nor prolactin concentration in rat serum. PR did not exhibit any affinity in vitro for dopaminergic, adrenergic, serotoninergic, GABAergic, muscarinic, adenosine (IC50 > 10 μM), and benzodiazepine receptors (IC50 > 1 μM) binding sites. It may be concluded that the mechanism of action of pramiracetam does not appear to be due to a direct action upon DA and 5-HT neurotransmitter systems or various brain receptors. PR (44 and 88 mg/kg i.p.) caused a significant increase in the rate of sodium-dependent high-affinity choline uptake (HACU) into rat hippocampal synptosomes in vitro. This was specific as no effect was observed in cerebral cortex and corpus striatum. These results would seem to indicate that PR is accelerating hippocampal acetylcholine turnover and thus septal-hippocampal cholinergic neuronal impulse flow. This effect could be at least partially responsible for the enhancement of cognition processes observed for this agent.

The effects of the antihypertensive drug CI-926 on rat brain norepinephrine (NE), dopamine (DA), and serotonin (5-HT) turnover and its in vitro affinity for several receptors were investigated. CI-926 (3-30 mg/kg intraperitoneally, i.p.) caused a dose-dependent increase in the rate of brain stem NE synthesis and increased the decline in NE after inhibition of its synthesis by alpha-methyl-p-tyrosine. These findings indicated that CI-926 increased brain NE turnover, probably as a compensatory response to central adrenoceptor blockade based on its nanomolar affinity for alpha 1-adrenoceptors and micromolar affinity for alpha 2-adrenoceptors. CI-926 also increased the rate of DA synthesis and DA metabolite levels; this indicates an increase in DA turnover. The latter effect of CI-926 is attributed to a compensatory response to DA-2 receptor blockade because no affinity for DA-1 relative to DA-2 receptors was found and the effect was antagonized by the DA agonist pergolide. CI-926 decreased brain 5-HT turnover, as indicated by reduced concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid and a reduced rate of 5-HT synthesis, effects characteristic of centrally acting 5-HT agonists. Based on its affinity for 5-HT-1A receptors versus 5-HT-1B and 5-HT-2, the decrease in 5-HT synthesis and release is interpreted as evidence of 5-HT-1A receptor activation. These findings indicate that besides peripheral alpha 1-adrenergic blockade, an interference of CI-926 with central adrenergic and serotoninergic neurotransmission may contribute in part to an explanation of its antihypertensive properties.

The administration of the stable adenosine analog (R)-N-(1-methyl-2-phenylethyl)adenosine (R-PIA) caused a dose-dependent decrease in the accumulation of striatal dihydroxyphenylalanine (DOPA) levels following DOPA decarboxylase inhibition, with the minimum effective dose being 0.2 mg/kg, i.p.; 5'-deoxy-5'-(ethylamino)-5'-oxoadenosine (NECA) at 0.5 mg/kg, i.p., was also active indicating that in vivo R-PIA and NECA were decreasing striatal dopamine (DA) synthesis. Both R-PIA and NECA also decreased striatal levels of the DA metabolite 3-methoxytyramine (3-MT), indicating a decreased release of DA which was consistent with their effects on DA synthesis. N-Cyclohexyladenosine (CHA) also decreased 3-MT levels. The S-isomer of PIA at an equipotent dose did not affect either DA synthesis or release. R-PIA (3 mg/kg, i.p.) antagonized the pargyline-induced increase in striatal 3-MT levels as did gamma-butyrolactone, further confirming a decreased release of striatal DA. The adenosine receptor antagonist 8-cyclopentyltheophylline antagonized the R-PIA induced-decrease in striatal DA synthesis, suggesting that the latter was mediated via adenosine receptors. It is concluded that the stable adenosine analogs R-PIA and NECA, at behaviorally active doses, are decreasing in vivo the rate of DA synthesis and release from rat striatal DA nerve terminals by an adenosine receptor-mediated effect.

(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanone (1) was found to have an antipsychotic-like profile in behavioral tests predictive of antipsychotic efficacy but, unlike available antipsychotic agents, did not bind in vitro to dopamine receptors. Upon further evaluation, 1 was found to cause clonic seizures in aged rodents. An examination of related structures revealed that 5-(substituted aminoacetamide) analogues of 1 shared this novel pharmacology and did not cause seizures. The synthesis and pharmacological evaluation of this series of compounds are described. Two compounds, 2-(diethylamino)acetamide (25) and 2-[[3-(2-methyl-1-piperidinyl)propyl]-amino]acetamide (38), were selected for examination in secondary tests. Like known antipsychotics both compounds reduced spontaneous locomotion in mice at doses that did not cause ataxia and inhibited conditioned avoidance selectively in both rats and monkeys. Unlike known antipsychotics neither 25 nor 38 elicited dystonic movements in haloperidol-sensitized cebus monkeys, a primate model of antipsychotic-induced extrapyramidal side effects. Biochemical studies indicated that these compounds act via a nondopaminergic mechanism. Neither 25 nor 38 bound to dopamine receptors in vitro or caused changes in striatal dopamine metabolism in vivo. In addition, they did not raise serum prolactin levels as do known antipsychotics. Although adverse animal toxicological findings have precluded clinical evaluation of these agents, the present results indicate that it is possible to identify at the preclinical level nondopaminergic compounds with antipsychotic-like properties.

The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]anilines with dopaminergic properties are described. One of these compounds, 3-[3-(4-phenyl-1-piperazinyl)propoxy]benzenamine (4c), has been identified as a selective dopamine (DA) autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. In addition, 4c possesses good oral activity in the Sidman conditioned avoidance test in squirrel monkeys, which is indicative of antipsychotic activity. In a primate model, 4c was found to lack the liability for extrapyramidal side effects usually associated with antipsychotic drugs.

The dopamine agonist profiles of 3,4-dihydro-3-(3-dipropylamino)-2H-1-benzopyran-6- and -8-ol (4 and 5, respectively) were examined. Both 4 and 5 exhibited greater relative affinity for receptors labeled with the dopamine agonist ligand [3H]propylnorapomorphine than for those labeled with the dopamine antagonist ligand [3H]haloperidol. Both compounds attenuated the stimulation of brain dopamine synthesis caused by gamma-butyrolactone (GBL) and decreased the firing rate of substantia nigra dopamine neurons in rats. This profile of activity, together with the ability of the dopamine antagonist haloperidol to reverse the inhibition of dopamine neuronal firing, indicate that both compounds are brain dopamine agonists.

The dopamine agonist profiles of 3,4-dihydro-3-(3-dipropylamino)-2H-1-benzopyran-6- and -8-ol (4 and 5, respectively) were examined. Both 4 and 5 exhibited greater relative affinity for receptors labeled with the dopamine agonist ligand [3H]propylnorapomorphine than for those labeled with the dopamine antagonist ligand [3H]haloperidol. Both compounds attenuated the stimulation of brain dopamine synthesis caused by gamma-butyrolactone (GBL) and decreased the firing rate of substantia nigra dopamine neurons in rats. This profile of activity, together with the ability of the dopamine antagonist haloperidol to reverse the inhibition of dopamine neuronal firing, indicate that both compounds are brain dopamine agonists.