Lennart Florvall

Remoxipride, a new potential antipsychotic compound with selective anti-dopaminergic actions in the rat brain

The novel substituted benzamide, remoxipride, preferentially blocked apomorphine-induced hyperactivity with weak effects on stereotypies. The potency of remoxipride was about 50 times higher than that of sulpiride. Remoxipride caused a weak, atypical form of catalepsy and showed a high separation between the ED50 for blockade of apomorphine-induced hyperactivity and the ED50 for induction of catalepsy (ratio 24). Remoxipride was shown to be a selective dopamine D2 receptor antagonist since it displaced [3H]spiperone (IC50 = 1570 nM) but not [3H]flupentixol (IC50 greater than 100 000 nM) in rat striatum, and did not inhibit striatal DA-sensitive adenylate cyclase in vitro (IC50 greater than 100 000 nM). Remoxipride is a potent antagonist of D2 receptors showing a dose-dependent blockade of [3H]spiperone and [3H]n-propylnorapomorphine in vivo binding with a potency equal to that of chlorpromazine. In contrast to haloperidol, remoxipride caused a preferential blockade of in vivo [3H]spierone binding in the mesolimbic DA rich areas and the substantia nigra with much less effect in the striatum. In addition, remoxipride produced a preferential increase of DA utilization following synthesis inhibition in the olfactory tubercle. Only minor changes in NA and 5-HT metabolism were observed while HVA and DOPAC levels were markedly elevated. Taken together, these results indicate that remoxipride is a potent, selective D2 receptor blocking agent with a preferential action in mesolimbic and extrastriatal dopamine-containing neurons.

Inhibition of monoamine oxidase in 5-hydroxytryptaminergic neurones by substituted p-aminophenylalkylamines.

1 A series of substituted p‐aminophenethylamines and some related compounds were examined with regards to the inhibition of monoamine oxidase (MAO) in vivo inside and outside 5‐hydroxytryptaminergic neurones in the rat hypothalamus. This was recorded as the protection against the irreversible inhibition of MAO produced by phenelzine by determining the remaining deaminating activity in the absence and presence of citalopram using a low (0.1 μM) concentration of [14C]‐5‐hydroxytryptamine (5‐HT) as substrate. 2 Some of the phenethylamines were much more potent inside than outside the 5‐hydroxytryptaminergic neurones. This neuronal selectivity was antagonized by pretreatment of the rats with norzimeldine, a 5‐HT uptake inhibitor, which indicates that these compounds are accumulated in the 5‐HT nerve terminals by the 5‐HT pump. 3 Selectivity was obtained for compounds with dimethyl, monomethyl or unsubstituted p‐amino groups. An isopropyl group appears to substitute for the dimethylamino group but with considerably lower potency. Compounds with 2‐substitution showed selectivity for aminergic neurones and this effect decreased with increased size of the substituent. The 2,6‐dichloro derivative FLA 365 had, however, no neuronal selective action but was a potent MAO inhibitor. Substitutions in the 3‐ and 5‐ positions decreased both potency and selectivity. 4 Prolongation of the side chain with one methylene group abolished the preference for the MAO in 5‐hydroxytryptaminergic neurones although the MAO inhibitory potency remained. The selectivity disappeared by increasing the α‐substituent to an ethyl group but remained for the α,α‐dimethyl substituted derivatives. 5 It is concluded that compounds which are (1) transported by the 5‐HT pump and (2) potent reversible MAO‐A inhibitors produce pronounced inhibition of MAO in 5‐hydroxytryptaminergic neurones.

Selective inhibition of monoamine oxidase by p-aminosubstituted phenylalkylamines in catecholaminergic neurones

The in vivo inhibition of monoamine oxidase (MAO) inside and outside noradrenergic and dopaminergic nerve terminals in the hypothalamus and striatum, respectively, was examined in the rat after oral administration of a series of substituted p-aminophenethylamines and some related compounds. This was achieved by measuring their ability to protect MAO from irreversible inhibition by phenelzine, determined by the deaminating activity of synaptosomal preparations in the absence and presence of maprotiline, a selective inhibitor of the uptake of noradrenaline, or of amfonelic acid, a potent inhibitor of the uptake of dopamine, with small (0.25 microM) concentrations of [14C]noradrenaline or [14C]dopamine as substrate. It was found that several of these compounds were much more potent in protecting MAO within the noradrenergic neurones than MAO in other cells. Since the inhibitors of the uptake of noradrenaline, desipramine and CPP 199 antagonized this preference for noradrenergic MAO it is concluded that these MAO inhibitors are accumulated in the noradrenergic neurones by the membranal uptake carrier. Hence the selectivity for MAO within noradrenergic neurones seems to reflect the ability of the compounds to be transported by this carrier. The structure-activity relationship obtained showed the greatest selectivity for the unsubstituted p-dimethylamino-(FLA 289), p-methylamino-(FLA 727) and p-amino-(FLA 334)-amphetamines, whereas the 2-fluoro compound (FLA 558) had the greatest potency. N,N-didesmethylamiflamine [FLA 668(+)] had an almost specific effect in the noradrenergic nerve terminals. The primary p-amino derivatives, FLA 334 and FLA 668, produced a marked selective protection of MAO in dopaminergic nerve terminals, whereas the tertiary and secondary derivatives had much less preference for dopaminergic MAO.(ABSTRACT TRUNCATED AT 250 WORDS)

Convenient Synthesis of Indolines by Reduction of Indoles With Sodium Cyanoborohydride in Carboxylic Acids

Abstract The reduction of indoles to indolines has received considerable attention during the l a s t few years1,2. A recent report from Gribble et al 3, 4 has shown that sodium borohydride in neat acetic acid or formic acid reduces the indole double bond and at the same time alkylates the nitrogen to give Nalkyl indolines, while sodium cyanoborohydride in acetic acid or sodium borohydride in trifluoroacetic acid only reduces the double bond of indole to give indoline.

A PLS quantitative structure-activity relationship study of some monoamine oxidase inhibitors of the phenyl alkylamine type

Abstract The PLS method is used to derive improved quantitative structure-activity relationships for some monoamine oxidase (MAO) inhibitors of the phenyl alkylamine type. The established models for in vivo responses in NA, DA and 5-HT neurons indicate that small, electron-withdrawing substituents in the ortho and meta positions of the phenyl ring give compounds with high activities. An ( S )-configuration and an unsubstituted alkyl side chain also favor this objective. An N -methyl amino group in the para position gives compounds with high potency. The established models do not contain any outliers to indicate that these inhibitors form a rather uniform group with respect to the mechanism of action, metabolic pathways and distribution.

Prodrugs of neuron-selective monoamine oxidase inhibitors: amino acid derivatives of 1-(4-aminophenyl)-2-aminopropanes

Six amino acid derivatives of 1-(4-aminophenyl)-2-aminopropanes and their parent amines were synthezised and tested for their potency and selectivity in inhibiting monoamine oxidase (MAO) in vitro and in vivo. The amino acid derivatives were 300–1000 times less potent than the parent amines in inhibiting the MAO-A activity in a rat brain mitochondrial preparation in vitro. All compounds, except the (R)-valinamide derivative (22), were potent inhibitors of MAO in the rat brain in vivo and were, like the parent amines markedly more potent within the monoaminergic neurons than in other neurons. The glycinamide derivative 7 showed the largest difference between intra- and extra-neuronal inhibition in serotonergic neurons. The time course of the inhibitory effect of 7 in vivo showed that it is a reversible inhibitor with a long duration.

Partial dopamine receptor agonists with different degrees of intrinsic activity within a series of 2-(4-aminophenyl)-N,N-dipropylethylamine derivatives: synthetic chemistry and structure-activity relationships

Summary A series of 2-(4-aminophenyl)- N,N -dipropylethylamine derivatives were synthesized and tested for in vivo intrinsic activity at brain dopamine receptors in the rat. Differences in the sensitivity of dopamine receptors pre- and post-synaptically in the reserpine-treated rat were used to estimate the intrinsic activity of the various compounds as dopamine receptor agonists. Thus, the ability of the compounds to antagonize reserpine-induced increase in neostriatal dopamine synthesis and the suppression of spontaneous locomotor activity were taken as pre-and post-synaptic indices, respectively. The compounds in the present series display a gradient of intrinsic activity depending on the substituents in the aromatic ring. The presence of an amino group or an appropriate acylamino group in the 4-position was found to be critical for the biological activity of these compounds as agonists or antagonists. The introduction of halogen or a trifluoromethyl group in the 3-position resulted in high intrinsic activity (ie, agonist activity). The incorporation of a methyl group in the 3-position or halogens in the 3,5-positions resulted in a gradual decrease in intrinsic activity at rat brain dopamine receptors resulting in a series of compounds ranging from a full agonist to dopamine receptor blockade.

In vivo characterization of novel full and partial 2-(4-aminophenyl)-N, N-dipropylethylamine dopamine D2 receptor agonists

Behavioral and biochemical techniques were used to compare the in vivo intrinsic efficacy of two new 2-(4-aminophenyl)-N, N-dipropylethylamine dopamine D(2) receptor agonists, 2-(4-amino-3-trifluoromethylphenyl)-N-N-dipropyl-ethylamine (NBF-203) and 2-(4-amino-3-bromo-5-trifluoromethylphenyl)-N-N-dipropylethylamine (NBF-234). Adult male Sprague-Dawley rats were used as experimental animals. NBF-203 was characterized as a full dopamine D(2) receptor agonist, whereas NBF-234 displayed properties of a partial agonist, or antagonist, at dopamine D(2) receptors. Thus, NBF-203 produced effects similar to those of apomorphine in models for dopamine synthesis, release and turnover. As a strong indication of markedly less intrinsic efficacy, the administration of NBF-234 did not result in antagonism of reserpine-induced suppression of locomotor activity in the presence of (+/-)-1-phenyl-2,3,4,5, -tetrahydro-(1H)-3-benzazepine-7,8-diol HCl (SKF-38393)-induced dopamine D(1) receptor activation. The present series of compounds offer the possibility of adjusting intrinsic efficacy at dopamine D(2) receptors, and such fine-tuning could be an important strategy in the search for optimal antipsychotic or antiparkinson drugs within the partial dopamine D(2) receptor agonist concept.