The dopamine D1 receptor agonist (S)-[¹¹C]N-methyl-NNC 01-0259 is not sensitive to changes in dopamine concentration--a positron emission tomography examination in the monkey brain.

Dopamine D2 receptor positron emission tomography (PET) radioligands have proven useful for indirect assessment of the endogenous dopamine concentration in the living brain. On the contrary, dopamine D1 receptor antagonist radioligands have shown no sensitivity to changes in the dopamine concentration. A recent approach to enhance the sensitivity of radioligands to the dopamine concentration has been the development of dopamine D2 receptor agonist radioligands. The aim of this study was to evaluate the dopamine sensitivity of a dopamine D1 receptor agonist radioligand. For this purpose, we developed (S)-[¹¹C]N-methyl-NNC 01-0259 ((S)-[¹¹C]1) and characterized the receptor binding of (S)-[¹¹C]1 using in vitro receptor binding assays and in vivo PET measurements in monkeys. In vitro, both enantiomers of 1 were partial dopamine D1 receptor agonists, with (S)-1 having a 10-50 times higher affinity than (R)-1. PET studies in monkey confirmed the stereoselectivity of [¹¹C]1 in vivo. In monkey, administration of the dopamine D1-like receptor antagonist (R)-(+)-SCH 23390 decreased the striatal binding potential of (S)-[¹¹C]1 by 97%, but administration of the dopamine concentration enhancer d-amphetamine did not affect (S)-[¹¹C]1 binding. We conclude that the agonist (S)-[¹¹C]1 provides specific binding to dopamine D1-like receptors, possibly representing binding to the high-affinity state of the receptors. The partial dopamine D1 receptor agonist radioligand has, however, no enhanced sensitivity to endogenous dopamine concentrations in comparison with antagonist radioligands.

Smoking increases the incidence of complicated diverticular disease of the sigmoid colon.

BACKGROUND AND AIMS: The aim of this study was to establish whether smoking is associated with complicated diverticular disease and adverse outcomes of operative treatment of diverticular disease. Smoking has been associated with increased rate of perforations in acute appendicitis as well as failure of colonic anastomosis in patients resected for colonic tumours. It has also been suggested that smoking is a risk factor for complicated diverticular disease of the colon. MATERIAL AND METHODS: Retrospective investigation of records of 261 patients electively operated for diverticular disease in Helsinki University Central Hospital during a period of five years. RESULTS: The smokers underwent sigmoidectomy at a younger age than the non-smokers (p = 0.001) and they had an increased rate of perforations (p = 0.040) and postoperative recurrent diverticulitis episodes (p = 0.019). CONCLUSIONS: We conclude that smoking increases the likelihood of complications in diverticulosis coli. The development of complicated disease also seems to proceed more rapidly in smokers.Key words: Sigmoid resection; laparoscopy; laparoscopic sigmoidectomy; smoking and diverticular disease; complicated diverticular disease; diverticulitis.

Robustness of a continuous direct compression line against disturbances in feeding.

The aim of the current study was to characterize the robustness of an integrated continuous direct compression (CDC) line against disturbances from feeding, i.e. impulses of API and short step disturbances. These disturbances mimicked typical variations that can be encountered during long-term manufacture. The study included a primary formulation, with API of standard particle size, which was manufactured at 5 and 10 kg/h production rates, and a modified formulation, with API of large particle size, which was manufactured at 5 kg/h production rate. Overall, the CDC line smoothened all the disturbances, fulfilling the USP uniformity of dosage units (UDU) limit for single tablets. However, runs with the modified formulation failed the pharmacopoeia UDU requirements for the entire run due to high variation between tablets. The primary formulation passed the requirements in all cases. The residence time distribution (RTD) results indicated that the primary formulation allowed better smoothening ability, and an increase in production rate led to poorer smoothening due to shorter RTD. The RTDs revealed that a substantial part of back-mixing took place after the blender. Thus, the tablet press has an important role in smoothening disturbances longer than the mean residence time of the blender, which was very short.

Is the beneficial antidepressant effect of coadministration of pindolol really due to somatodendritic autoreceptor antagonism?

BACKGROUND: We investigated the combination of selective serotonin reuptake inhibitors (SSRIs) with the beta-adrenoceptor/serotonin 1A (5-HT(1A)) antagonist pindolol, based on the concept that 5-HT(1A) receptor blockade would eliminate the need for desensitization of presynaptic 5-HT(1A) receptors and therefore hasten the onset of action and improve the efficacy of SSRIs. However, since pindolol plasma levels after 2.5 mg three times a day are about 60 nmol/L, and the K(i) for the 5-HT(1A) receptor is 30 nmol/L, it is questionable whether pindolol levels in the brain would be sufficient to antagonize 5-HT(1A) receptors. Using microdialysis in the guinea pig, we correlated brain and plasma levels of pindolol with its capability of augmenting paroxetine-induced increases in brain 5-HT levels. In addition, central beta-receptor antagonism of pindolol was studied by investigating blockade of beta-agonist-induced increases in brain cyclic adenosine monophosphate (cAMP) formation. METHODS: Using microdialysis and jugular vein catheterization, we studied the ability of systemically administered pindolol to antagonize central 5-HT(1A) and beta-adrenoceptors, while simultaneously monitoring pindolol plasma and brain concentrations. RESULTS: Augmentation of paroxetine-induced increases in extracellular 5-HT levels in the ventral hippocampus was only observed at steady state plasma levels exceeding 7000 nmol/L (concurrent brain levels 600 nmol/L). In contrast, antagonism of beta-agonist-induced increases of brain cAMP levels was already observed at pindolol plasma levels of 70 nmol/L (concurrent brain levels < 3 nmol/L). CONCLUSIONS: At plasma levels that are observed in patients after 2.5 mg three times a day ( approximately 60 nmol/L), pindolol produces only a partial blockade of presynaptic 5-HT(1A) autoreceptors and does not augment the SSRI-induced 5-HT increase in the guinea pig brain. It is therefore very unlikely that the favorable effects of combining pindolol with SSRIs, as reported in a number of clinical studies, are due to 5-HT(1A) antagonism. Since pindolol completely blocks central beta-adrenoreceptors at clinically relevant plasma levels, it is possible that beta-adrenoceptor antagonism is involved in mediating pindolol's beneficial effects.

A molecular mechanics approach to the understanding of presynaptic selectivity for centrally acting dopamine receptor agonists of the phenylpiperidine series.

Molecular mechanics (MMP2) calculated geometries and conformational energies have been employed in an attempt to elucidate the molecular basis for presynaptic dopamine receptor selectivity of centrally acting agonists of the phenylpiperidine series. A receptor interaction model based on the McDermed receptor concept, on superimpositions of calculated structures, and on conformational analysis is presented. The model focuses on the interaction between N-alkyl substituents and the receptor. From comparisons with rigid structures having either agonistic or antagonistic properties it is concluded that the presynaptically selective compound (S)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [S)-3PPP) is acting as an agonist in one rotameric form and as an antagonist in another one. The selectivity of (S)-3PPP and the nonselectivity of its enantiomer are suggested to be due to differences in the interactions between N-alkyl substituents and the receptor. The receptor model presented led to the hypothesis that the piperidine ring in the compounds studied should be equivalent to a N-methyl group in its receptor interactions. Examples are given in support of this idea. Presynaptic selectivity was predicted for an aminotetralin derivative and was also observed in subsequent testing.

Conformational analysis of 2-aminoindans and 2-(aminomethyl)indans in relation to their central dopaminergic effects and a dynamic dopamine receptor concept.

Conformational analyses on differently substituted 2-aminoindans of significant pharmacological interest were carried out by the molecular mechanics method (MM2). An X-ray structure of (R)-4-methoxy-2-aminoindan has shown the ammonium nitrogen [-)-D-tartaric acid salt) in an axial position. From comparison with other, highly potent, centrally acting dopamine (DA) receptor agonists, it can be predicted that the active enantiomer (R)-4-hydroxy-2-(di-n-propylamino)indan should have its nitrogen atom in an equatorial position. This places it close to the aromatic ring plane, which is one of several prerequisites for potent DA receptor agonism. MM2 correctly calculates (R)-4-methoxy-2-aminoindan and (R)-4-hydroxy-2-(dialkylamino)indan to be more stable in the N-axial and N-equatorial conformations, respectively. Conformational analysis of the dimethyl model compound of the moderately potent dopaminergic phenylpropylamine analogue 4-hydroxy-2-[(di-n-propylamino)methyl]indan was also carried out, in order to see if any conformations of this compound satisfy the requirements for dopaminergic agonism. Two such stable conformations were found.

Synthesis and pharmacological evaluation of triflate-substituted analogues of clozapine: identification of a novel atypical neuroleptic.

The trifluoromethanesulfonyloxy (TfO) analogues 3 and 4 of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine (clozapine, 1) and its 2-chloro isomer (iso-clozapine, 2), respectively, were synthesized via their OMe and OH analogues with the conventional synthetic method of the tricyclic dibenzodiazepines and evaluated pharmacologically along with their parent drugs. The binding profile of the 2-OTf analogue (4) is comparable to the binding profile of 1, although the affinity for the dopamine (DA) D2 receptors is higher (IC50 values are 31 nM and 330 nM for compounds 4 and 1, respectively). Interestingly, no notable affinity for muscarinic receptors could be detected in compound 4. On the contrary, the 8-OTf analogue 3 only displayed affinity for muscarinic M1 receptors (IC50 value 35 nM) and no affinity (IC50 value > 500 nM) for the other receptors tested. The 10 mumol/kg sc dose, but not the 10 mumol/kg po dose, of compound 4 stimulated the output of DA. Increases of 80% and 35% in DOPAC output from the dorsal striatum were seen after sc and po administrations of 10 mumol/kg of compound 4, respectively. Doses up to 100 mumol/kg of compound 3 had no effect on either parameter. Doses up to 100 mumol/kg of compound 4 were not cataleptogenic, but significantly decreased apomorphine-induced locomotor activity. In conclusion, compound 4 (GMC1-169) is a new clozapine-like neuroleptic candidate, which is lacking anticholinergic properties and displays a higher potency, as compared to clozapine (1) itself.

The dopaminergic moiety of the ergots: a controversial topic studied with molecular mechanics.

Conformational analyses of the side chain of model compounds of the in vivo active dopamine receptor agonist 4-[2-(di-n-propylamino)ethyl]indole (DPAI) were performed with molecular mechanics calculations. The results from these calculations, together with the possibility of meta hydroxylation of indoles in vivo, led to the proposal of fitting 6-hydroxy-4-[2-(di-n-propylamino)ethyl]indole (6-OH-DPAI), (S)-5-hydroxy-N,N-dialkyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-ylami nes and (S)-5-hydroxy-2-(dialkylamino)tetralins in a common concept, considering both stereochemistry and hydrogen-bond function in such an overlap. This study emphasizes the importance of considering both conformational analysis and the possibilities of metabolic activation when performing structure-activity studies based on flexible compounds and in vivo data. The answer to the question as to which part of the ergot molecule is responsible for its dopaminergic effect is thus ambiguous. It is possible that the pyrrolylethylamine moiety of the ergots contributes to both in vitro and in vivo effects, and that their 13-OH metabolites contribute, possibly significantly, to their in vivo effects.

Pivaloyl esters of N,N-dialkylated dopamine congeners. Central dopamine-receptor stimulating activity.

In order to test for dopamine-receptor stimulating activity a new, sensitive biochemical screening method was designed. For behavioral studies and for determination of the duration of action on the compounds, motor activity measurements were used. O,O'-Dipivaloyl-N,N-dipropyldopamine (4) was the only derivative of a series of dipivaloyl-N,N-dialkyldopamines studied that showed any significant activity. However, the monopivaloyl ester 2-(3-pivaloyloxyphenyl)-N,N-dipropylethylamine (8) seemed to be more potent. The same relationship was found for the corresponding phenols, N,N-dipropyldopamine (3) and 2-(3-hydroxyphenyl)-N,N-dipropylethylamine (7), although both were more active than their pivaloyl esters.

Occurrence and pharmacological significance of metabolic ortho-hydroxylation of 5- and 8-hydroxy-2-(di-n-propylamino)tetralin.

Aromatic ortho-hydroxylation in the liver might be one of several possible reasons for the low bioavailabilities of the potent, centrally acting dopaminergic and serotoninergic agonists 5- and 8-hydroxy-2-(di-n-propylamino)tetralin, respectively. In vitro and in vivo experiments showed that such an oxidative metabolism did indeed take place. However, the amount of hydroxylated metabolites found in the brain was estimated to represent only 0.3% of the total amount of drug administered. The O-methylation rates of these catechols were also measured in vitro and showed that 5,6-dihydroxy-2-(di-n-propylamino)tetralin is a poor substrate for catechol O-methyltransferase (COMT) and that its 7,8-dihydroxy isomer is virtually devoid of substrate activity. No O-methylated metabolites were detected in the in vivo samples analyzed. A new synthetic strategy was applied to achieve the isomeric catechols studied. 5-Methoxy- or 8-methoxy-2-(di-n-propylamino)tetralin was lithiated in the ortho position and the metalated species was subsequently quenched in nitrobenzene, yielding the methoxy hydroxy isomers, which were heated in 48% aqueous HBr to achieve the corresponding catechols.

GRID/GOLPE 3D quantitative structure-activity relationship study on a set of benzamides and naphthamides, with affinity for the dopamine D3 receptor subtype.

In the search for drugs against schizophrenia and depression without extrapyramidal side effects, compounds that selectively antagonize the dopamine D3 receptor subtype are thought to be a solution. In order to create a model with which the D3 activity can be predicted and that can generate new ideas for future synthesis, we performed a comparative molecular field analysis (CoMFA). In our model 30 ligands were described quantitatively in the GRID program, and the model was optimized by selecting only the most informative variables in the GOLPE program. We found the predictive ability of the model to increase significantly when the number of variables was reduced from 25110 to 784. A Q2 of 0.65 was obtained with the final model, confirming the predictive ability of the model. By studying the PLS coefficients in informative 3D contour plots, ideas for the synthesis of new compounds can be generated.

Pre- and postsynaptic dopaminergic activities of indolizidine and quinolizidine derivatives of 3-(3-hydroxyphenyl)-N-(n-propyl)piperidine (3-PPP). Further developments of a dopamine receptor model.

Pre- and postsynaptic dopaminergic activities of a series of indolizidine and quinolizidine analogues of 3-(3-hydroxyphenyl)-N-(n-propyl)piperidine (3-PPP) have been studied. The pharmacological data have been interpreted in terms of a previously reported model for interactions with dopamine pre- and postsynaptic D2-receptors and molecular mechanics (MM2(85] calculated geometries and conformational energies. The model has been further developed with respect to the receptor topography in the vicinity of the nitrogen binding site. In particular, a novel spatial orientation of the important "propyl cleft" has been proposed. This cleft is suggested to be located mainly above a plane through the receptor-bound substrate. The biologically active agonist and antagonist conformations of the enantiomers of 3-PPP have been reinvestigated.

Quantitative structure-activity relationships and eudismic analyses of the presynaptic dopaminergic activity and dopamine D2 and sigma receptor affinities of 3-(3-hydroxyphenyl)piperidines and octahydrobenzo[f]quinolines.

Data from the preceding paper were examined by QSAR and eudismic analyses. A fair parabolic relationship was found between the lipophilicity (measured by a RP-HPLC method) and the sigma-receptor affinity of 3-(3-hydroxyphenyl)piperidines (3HPP derivatives) and octahydrobenzo[f]quinolines (OHBQ derivatives). As far as the dopamine D2 receptor is concerned, the trans-7-hydroxy-OHBQ derivatives show a 10-fold higher affinity than the eutomeric S enantiomers of 3HPP derivatives, once lipophilicity has been accounted for. This difference in affinity is suggested to correspond to the energy necessary for the 3HPP derivatives to adopt the receptor-bound conformation. The R enantiomers of 3HPP derivatives display no apparent increase in D2 affinity with increasing lipophilicity, and indeed the eudismic index in this series increases with affinity (eudismic affinity quotient = 0.70), in agreement with a recent model of the binding of N-propyl-3HPP (3PPP) enantiomers to the D2 receptor. The selectivity in sigma/D2 affinities was found to depend on both lipophilicity and configuration of the ligands; thus, the selectivity is maximal for log kw values of ca. 1.7-2.1 and is much larger for the R than for the S enantiomers of 3HPP derivatives.

N-substituted 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines and 3-phenylpiperidines: effects on central dopamine and sigma receptors.

N-Substituted analogues of trans-7- and trans-9-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (trans-7- and trans-9-OH-OHBQ) were tested for dopamine (DA) D2 receptor affinity by using in vitro [3H]spiperone and in vivo 5,6-di-n-Pr-ADTN binding assays. Potencies at central pre- (auto-) and postsynaptic DA receptors were determined by a biochemical and a behavioral method, respectively. Corresponding data were included for analogous, resolved 3-(3-hydroxyphenyl)piperidines and a few other substituted, racemic 3-phenylpiperidines. Beside the central dopaminergic effects of these compounds, previously reported sigma receptor affinity data [[3H]-(+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine; [3H]-(+)-3-PPP] were also taken into account for a comparison of the structure-activity/affinity relationships of these compounds at these two receptor types. Larger N-substituents in both phenylpiperidines and OHBQs increase both pre- and postsynaptic dopaminergic activity. An n-propyl group gives high dopaminergic efficacy at both receptor sites (pre- and postsynaptic) in all series. However, even higher dopaminergic potency is observed for trans-7-OH-OHBQs and (S)-3-(3-hydroxyphenyl)piperidines with N-substituents larger than n-propyl. In contrast, trans-4-n-Bu-9-OH-OHBQ is inactive, and (R)-3-(3-hydroxyphenyl)-N-n-butylpiperidine is less active at central DA receptors than its corresponding n-propyl analogue. This implies interesting differences in N-substituent sensitivity for the different classes of compounds with respect to the direction of their respective N-substituents at the drug-receptor interaction. The stereochemical and steric demands for sigma receptor affinity are much less stringent. The general trend is that, up to a certain size, the more lipophilic the N-substituent, the higher the affinity for sigma receptor sites.

Enantiomers of 3-(3,4-dihydroxyphenyl)- and 3-(3-hydroxyphenyl)-N-n-propylpiperidine: central pre- and postsynaptic dopaminergic effects and pharmacokinetics.

This study emphasizes the importance of the metabolic conversion of the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) into their catechol analogues, the enantiomers of 3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine. These isomers are both shown to be excellent substrates for COMT, with a slight preference for the S-(-) enantiomer. Assessment of the dopaminergic activity of these catechols and the results from the determination of brain levels of the enantiomers of 3-PPP and their metabolites indicate that the metabolites probably do not alter the pharmacological profiles established for (R)-(+)- and (S)-(-)-3-PPP. The conversion of the monophenols into catecholic metabolites is only 1-5%, and the further conversion of these catecholic metabolites into methoxylated analogues is very rapid. However, the very interesting observation was made that, when inhibiting COMT by means of tropolone and subsequently treating the rats with high doses of (S)-(-)-3-PPP (ip), postsynaptic dopaminergic activity was elicited. This has never been seen for (S)-(-)-3-PPP without tropolone pretreatment and might indicate that, in this special case, the catecholic metabolite affects the in vivo pharmacological profile of (S)-(-)-3-PPP.

Resolved cis-10-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinoline : central serotonin stimulating properties.

cis-10-Hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b -octahydrobenzo[f]quinoline (4) is a centrally acting serotonin (5-HT) receptor agonist of moderate potency. Due to its semirigid character and the obvious similarity between (4aR,10bS)-4 and more potent, centrally acting 5-HT receptor agonist cis-(1S,2R)-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (2), we carried out the preparation (via resolution of 6, a precursor of 4) and the pharmacological testing of the enantiomers of 4. We were able to show that the active enantiomers of 4 and 2 coincide in terms of stereochemistry, i.e., that it is the 4aR,10bS enantiomer of 4 that is the more active one. The absolute configuration was assigned on the basis of single-crystal X-ray analysis of the precursor (+)-6 of the active enantiomer (-)-4. Conformational analysis with molecular mechanics (MM2) calculations were performed on the N-methyl analogues of compounds cis-(1S,2R)-2 (cis-(1S,2R)-3) and cis-(4aR,10bS)-4 (cis-(4aR,10bS)-7). Both ammonium and free amine forms were subjected to these calculations. The results show a preference for the N-equatorial conformation, which is corroborated by the X-ray structure of (+)-6.HCl. The relatively low potency of compound cis-(4aR,10bS)-4 might be explained by unfavorable direction of the N-lone pair (or ammonium hydrogen) bond in this compound as compared to cis-(1S,2R)-2 and trans-(4aR,10bR)-5, which can be predicted to be the more active enantiomer of compound 5.

Resolved 6,7,8,9-tetrahydro-N,N-dimethyl-3H-benz[e]indol-8-amine: central dopamine and serotonin receptor stimulating properties.

The enantiomers of 6,7,8,9-tetrahydro-N,N-dimethyl-3H-benz[e]indol-8- amine (1a) were prepared and tested for their actions on central dopamine and serotonin (5-HT) receptors. The dopaminergic effects were shown to reside in the (1)-R enantiomer. It was shown that compound 1a and its (+)-R enantiomer possess potent central 5-HT1A receptor stimulating properties.

C1-Methylated 5-hydroxy-2-(dipropylamino)tetralins: central dopamine-receptor stimulating activity.

C1-Methylated derivatives of the potent dopaminergic agonist 5-hydroxy-2-(di-n-propylamino)tetralin (6) have been synthesized and tested for central dopamine (DA) receptor stimulating activity, by using biochemical and behavioral tests in rats. Both cis- and trans-5-hydroxy-1-methyl-2-(di-n-propylamino) tetralin (4 and 3) may be classified as central DA-receptor agonists, albeit of lower potency than 6. The results obtained indicate that both 4 and 3 display DA-autoreceptor stimulation capacity. However, only one of the isomers, trans-3, is able to elicit clear-cut postsynaptic DA receptor agonist actions at larger doses. 5-Hydroxy-1,1-dimethyl-2-(n-propylamino) tetralin (5) was found to be inactive.

8-Hydroxy-2-(alkylamino)tetralins and related compounds as central 5-hydroxytryptamine receptor agonists.

A series of 2-(alkylamino)tetralins related to 8-hydroxy-2-(di-n-propylamino)tetralin (21) were prepared and tested as dopamine (DA) and 5-hydroxytryptamine (5-HT) receptor agonists. Several of the compounds were potent 5-HT agonists devoid of DA-mimetic effects. N-Ethyl or N-propyl substitution of 8-hydroxy-2-aminotetralin gave the most potent agonists. It was shown that the most potent compound, (+)-21, has the 2R configuration. 5,8-Di-methoxy-2-(di-n-propylamino)tetralin (31) was found to be a weak DA agonist devoid of 5-HT activity. The corresponding indan derivative, 4,7-dimethoxy-2-(di-n-propylamino)indan (39), has been reported to be active on both DA and 5-HT receptors. The 5-HT-stimulating properties of compounds 21 and 39 as compared to the incapability of compound 31 to activate the 5-HT receptor is tentatively explained by the assumed mode of binding of the compounds to the 5-HT receptor.

Resolved monophenolic 2-aminotetralins and 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines: structural and stereochemical considerations for centrally acting pre- and postsynaptic dopamine-receptor agonists.

A detailed structure-activity relationship is revealed for resolved, centrally acting dopamine (DA) agonists acting on both pre- and postsynaptic DA receptors. The compounds resolved are 5- and 7-hydroxy-2-(di-n-propylamino)tetralin and cis- and trans-7-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinoline. By the superimposition of the structures of the more active enantiomers of these compounds with those of known dopaminergic agonists, apomorphine and ergolines, a new DA-receptor model is proposed as an outgrowth of current DA-receptor theories. One of the most important concepts of this receptor model is its emphasis on the possible positions taken by the N-substituents of dopaminergic compounds. One of these positions i sterically well defined while the other direction is sterically less critical. The model has been used to explain the lack of dopaminergic activity of some previously reported structures and also to predict properties of novel structures, including inherent chirality, which should be active at DA receptors. Hopefully, this heuristic DA-receptor model will lead to the discovery of more selective and potent pharmacological tools, which ultimately might lead to the development of therapeutic agents for treating diseases of dopaminergic function in the central nervous system.