ABSTRACT
5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D(3) receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D(3) antagonists. Thus, combinations of various alkyl groups were generally inactive at the D(3) receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D(3) binding affinity, the D(2) affinity is also enhanced, resulting in a less than 4-fold preference for the D(3) receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D(3) antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH(3).Me(2)S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et(3)SiH to give the desired product 3 in good overall yield of ( approximately 65%) from the indanone 5c.
Subject(s)
Dopamine Antagonists/chemical synthesis , Indans/chemical synthesis , Receptors, Dopamine D2/drug effects , Animals , Binding, Competitive , CHO Cells , Cell Division/drug effects , Cricetinae , Dopamine Antagonists/chemistry , Dopamine Antagonists/pharmacology , Hepatocytes/drug effects , Hepatocytes/metabolism , In Vitro Techniques , Indans/chemistry , Indans/pharmacology , Male , Motor Activity/drug effects , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D3 , Structure-Activity RelationshipABSTRACT
We have discovered two substituted 4-aminopiperidine compounds having high in vitro affinity and selectivity for the human dopamine D1 receptor. Both compounds, 3-ethoxy-N-methyl-N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinylamine (U-99363E), and its 3-isopropoxy analog (U-101958), were found through a routine receptor binding screen. The determined affinities (Ki) of these compounds for the cloned human dopamine D4 receptor were 2.2 and 1.4 nM, respectively. They exhibited at least 100-fold lower affinities for dopamine D2 and for other dopaminergic, serotonergic and adrenergic receptors. Both compounds were found to antagonize quinpirole-induced mitogenesis in Chinese hamster ovary cells expressing the human dopamine D4 receptor. In spite of their poor metabolic stability and low bioavailability. U-99363E and U-101958 appear to be among the first high-affinity, highly selective dopamine D4 receptor antagonists reported, and may have utility in in vitro investigations requiring selective tagging or blockade of dopamine D4 sites.
Subject(s)
Aminopyridines/pharmacology , Piperidines/pharmacology , Receptors, Dopamine D2/drug effects , Aminopyridines/metabolism , Animals , CHO Cells , Cricetinae , Humans , Mitosis/drug effects , Piperidines/metabolism , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D4 , Recombinant Proteins/drug effects , Recombinant Proteins/metabolism , Signal TransductionABSTRACT
The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.
Subject(s)
Aminoquinolines/chemical synthesis , Dopamine Agonists/chemical synthesis , Imidazoles/chemical synthesis , Serotonin Receptor Agonists/chemical synthesis , Aminoquinolines/metabolism , Aminoquinolines/pharmacology , Animals , Dopamine Agonists/metabolism , Dopamine Agonists/pharmacology , Imidazoles/metabolism , Imidazoles/pharmacology , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Methylamines/chemical synthesis , Methylamines/pharmacology , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Rabbits , Rats , Rats, Sprague-Dawley , Receptors, Dopamine/metabolism , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/metabolism , Serotonin Receptor Agonists/pharmacology , StereoisomerismSubject(s)
Antipsychotic Agents/chemical synthesis , Dopamine Antagonists/chemical synthesis , Dopamine D2 Receptor Antagonists , Piperazines/chemical synthesis , Sulfonamides/chemical synthesis , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Biological Availability , CHO Cells , Cricetinae , Dopamine Agonists/pharmacology , Dopamine Antagonists/chemistry , Dopamine Antagonists/metabolism , Dopamine Antagonists/pharmacology , Ergolines/antagonists & inhibitors , Humans , Molecular Structure , Piperazines/chemistry , Piperazines/metabolism , Piperazines/pharmacology , Protein Binding , Quinpirole , Receptors, Adrenergic/metabolism , Receptors, Dopamine D4 , Receptors, Serotonin/metabolism , Schizophrenia/drug therapy , Sulfonamides/chemistry , Sulfonamides/metabolism , Sulfonamides/pharmacologyABSTRACT
In order to explore further the structure-activity relationships of serotonergic and dopaminergic ligands, a series of enantiopure 5-, 7-, or 8-triflate (-OTf)-substituted 2-(monopropylamino)-tetralins have been synthesized and evaluated in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, the 8-OTf-substituted compound R-(+)-6 was found to be a potent and selective 5-HT1A (5-hydroxytryptamine) receptor agonist inducing a full-blown 5-HT syndrome in normal rats, while the corresponding 5-OTf-substituted compound S-(-)-12 was found to be a preferential dopamine (DA) autoreceptor agonist. A partial 5-HT syndrome was also observed for S-(-)-12, while the corresponding R-(+)-12 was found to be inactive at the DA and 5-HT receptors both in vitro and in vivo. Compounds 6 and 12 were found to be major urinary metabolites following oral administration of their dipropyl analogs (2 and 13, respectively). Thus 6 was proposed to be the metabolite responsible for the full-blown 5-HT syndrome seen after oral (but not subcutaneous) administration of 2. Similarly, 12 was proposed to be the metabolite responsible for the partial 5-HT syndrome seen after oral (but not subcutaneous) administration of 13. The bioavailability of R-(+)-6 (7.6 +/- 1.1%) appeared to be slightly lower than that of 2 (11.2 +/- 5.2%), although the in vitro metabolism of R-(+)-6 appeared to be slower than that of 2. Therefore first-pass metabolism was not thought to be the reason for the lower bioavailability of R-(+)-6, as compared to 2.
Subject(s)
Receptors, Dopamine/drug effects , Receptors, Serotonin/drug effects , Tetrahydronaphthalenes/pharmacology , Animals , Behavior, Animal/drug effects , Biological Availability , Cells, Cultured , Liver/drug effects , Liver/metabolism , Male , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Spectrum Analysis , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacokineticsABSTRACT
The racemic triflate derivatives 5-8 of the 5-, 6-, 7-, and 8-hydroxylated 2-(di-n-propylamino)-teralins 1-4 were shown to possess similar pharmacological profiles to their phenolic counterparts in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, subcutaneous administration of the 5-, 6-, and 7-triflates displayed essentially dopaminergic agonist properties, while the 8-triflate was shown to be a selective 5-HT1A receptor agonist. With respect to their agonist activities, the triflates were less potent than their phenolic analogs. The absolute oral bioavailability of compound 8 (8-triflate) was 4-5 times greater than the corresponding hydroxylated compound. Interestingly, in the in vivo biochemical assay compound 8 was found to be more potent after oral than after subcutaneous administration, indicating formation of one or more active metabolites. Following a study of the metabolism of compound 8 in rat hepatocytes, the monopropyl analog 9 was identified as the major metabolite and was surprisingly found to be more potent than compound 8. Oral administration of compound 5 (5-triflate) resulted in behavioral and biochemical effects indicative of mixed DA/5-HT1A agonist properties not seen after subcutaneous administration. These results may also be indicative of the formation of active metabolites.
Subject(s)
Receptors, Dopamine/metabolism , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/pharmacology , Serotonin Receptor Agonists/pharmacokinetics , Tetrahydronaphthalenes/pharmacology , Tetrahydronaphthalenes/pharmacokinetics , 8-Hydroxy-2-(di-n-propylamino)tetralin/analogs & derivatives , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacokinetics , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Administration, Oral , Animals , Behavior, Animal/drug effects , Biological Availability , Biotransformation , Chemical Phenomena , Chemistry, Physical , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/pharmacokinetics , Hydrocarbons, Fluorinated/pharmacology , Injections, Intravenous , Ligands , Liver/cytology , Liver/metabolism , Male , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Dopamine/drug effects , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/metabolism , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/metabolismABSTRACT
A simple method is described for the preparation of [6,7,7(-2)H3] sterols and steroids. The synthesis starts with a Δ(5)-sterol or steroid and involves preparation of the 6-oxo-3α,5α-cyclosteroid, base exchange in the presence of deuterium oxide to introduce two deuteriums at the C-7 position and sodium borodeuteride reduction of the 6-oxo group to introduce the third deuterium atom at C-6. Rearrangement of the [6,7,7(-2)H3]6α-hydroxy-3α,5α-cyclosteroid then gives the desired [6,7,7(-2)H3]-Δ(5) sterol or steroid. [6,7,7(-2)H3]Cholesterol, [6,7,7(-2)H3]pregnenolone and [6,7,7(-2)H3]3ß-hydroxyandrost-5-en-17-one were synthesized in this fashion and [6,7,7(-2)H3]progesterone was prepared from the [6,7,7(-2)H3]pregnenolone. Three examples of the use of these deuchromatography-mass spectrometry. The chrysophyte alga,Ochromonas malhamensis, was shown to be capable of introducing an extra methyl or ethyl group at C-24 of the side chain of [6,7,7(-2)H3]cholesterol to yield brassicasterol and poriferasterol, respectively. The ovary of the echinoderm,Asterias rubens, was demonstrated to metabolize [6,7,7(-2)H3]progesterone to yield mainly the 5α-isomers of pregnane-3,20-dione and 3ß-hydroxypregnan-20-one. However, the 5ß-isomers of these compounds were also detected as minor products for the first time as progesterone metabolites in this animal. Isolated oocytes of the frog,Xenopus laevis, produced a number of metabolites of [6,7,7(-2)H3]progesterone. In this report, two of them were shown to be 17α-hydroxy-pregn-4-en-3,20-dione and 20α-hydroxypregn-4-en-3-one.