Synthesis and central dopaminergic activities of (.+-.)-hexahydro-4H-indolo[3,4-gh][1,4]benzoxazine derivatives [(.+-.)-9-oxaergolines]

In a series of 7,8-dihydroxy-1-phenyltetrahydro-3-benzazepine dopamine receptor agonists introduction of a chloro or fluoro substituent into the 6-position increases dopaminergic potency. Also, in this series replacement of the 7-hydroxyl group with a halogen results in inversion of activity from dopamine receptor agonist to antagonist. The present study was aimed at exploring the possibility that the structure-activity observations in the 3-benzazepine series of dopaminergic agents might be extrapolated to another class of dopamine receptor agonists, the 2-aminotetralins. Thus, a series of chloro- and fluoro-substituted mono- and dihydroxylated 2-aminotetralins was prepared and evaluated for dopaminergic properties in D-1 and D-2 receptor-related tests. Introduction of a chloro substituent into the 8-position of the prototype of this series, i.e. 2-amino-6,7-dihydroxytetralin (ADTN), resulted in a compound with a high degree of selectivity for the D-1 subpopulation of dopamine receptors; it was equally or more potent than ADTN in the D-1 receptor-related tests with greatly decreased effectiveness in the tests involving D-2 receptors. A similar effect was observed with 8-fluoro-ADTN; however, the N-(4-hydroxyphenethyl)-N-propyl derivative 4g of the 8-chloro-substituted ADTN showed marked D-2 binding affinity. Conversely, introduction of a chloro substituent into the 5-position of ADTN markedly decreased D-1 receptor affinity and efficacy. This effect was not seen with the related 5-fluoro derivative, suggesting D-1 receptors are more sensitive to bulk in the 5-position of ADTN than are the D-2 receptors. Replacement of either the 6- or 7-hydroxyl groups of ADTN with a chloro or fluoro substituent, in contrast, did not parallel the response seen in the benzazepine series (i.e., the compounds uniformly demonstrated less receptor affinity and did not have dopamine receptor antagonist activity); however, the decrease in agonist potency was less marked in the case of 2-amino-6-fluoro-7-hydroxytetralins than in the chlorinated monohydroxyaminotetralins. Thus, a parallelism in structure-activity relationships in the benzazepine and aminotetralin series of dopamine receptor agonists was not observed. The differences may reflect altered modes of receptor binding in the two series.

Section: -Fluoro-7-methoxy-2-(dimethylamino)tetralin (27a)mentioning

confidence: 99%

Synthesis and dopaminergic activity of some halogenated mono- and dihydroxylated 2-aminotetralins

Weinstock¹,

De²,

Hj³

et al. 1986

“…The latter drug has been found to be considerably more efficacious than methotrexate or 10-deazaminopterin in a number of experimental murine tumor models.2 3'4 More recently it was shown to cause regressions in human mammary, lung, and colon tumor xenografts in nude mice. 5 Clinical trials have been initiated6 7for this agent, whose primary advantage appears to lie in its enhanced differential penetration and polyglutamylation in tumor vs. normal tissue.7 The enhanced transport takes place via an active-transport protein in the cell wall and represents one of the few examples whereby an antitumor drug takes advantage of a fundamental difference in the nature of this transport system between tumor and normal cells. The advantage of an enhanced polyglutamation of the compound once it enters the cell may result from diminished efflux of the polyglutamate species from the cell and also its increased in-hibitory potency for folate-dependent thymidine and purine synthetic enzymes.…”

mentioning

confidence: 99%

Synthesis and biological activity of resolved carbon-10 diastereomers of 10-methyl- and 10-ethyl-10-deazaminopterin

Ji¹,

Ph²,

Tagawa³

et al. 1986

Synthesis and evaluation of the antitumor drugs 10-methyl- and 10-ethyl-10-deazaminopterin (15a,b) were previously reported for the diastereomeric mixtures, lacking resolution at the C-10 position. In order to assess biological properties of the individual diastereomers, the C-10 isomers of 4-amino-4-deoxy-10-methyl- and 10-ethyl-10-deazapteroic acids (13a,b) were prepared by total synthesis. Coupling with L-glutamate afforded the appropriate diastereomers of the title compounds. Biochemical, transport, and cell growth inhibitory properties in L1210 cells and folate-dependent bacteria were measured. Differences were generally less than 2-fold between diastereomeric pairs, but a factor of 3 was noted for d,L-15b vs. l,L-15b in inhibition of DHFR from L1210 cells and in cytotoxicity toward L1210 cells. An in vivo comparison of the isomers of 15b with racemic compound against L1210 in mice did not show a significant efficacy difference (ILS) among the compounds. However, d,L-15b showed an acute toxicity about 2.5 times that of l,L-15b.

“…Recently, some 9-oxaergolines have been found to possess potent dopaminergic activity in vivo. 4,5 The structure-activity relationships for central dopaminergic activity of ergoline derivatives and related compounds indicate that the presence of an aromatic ring system replacing either the indole or the pyrrole ring is required.6 Also the presence of a tertiary and basic nitrogen atom, separated from the aromatic nucleus by two carbon atoms in a given conformation, is essential. The junction of the rings C and D must be trans, and the IV-n-propyl group frequently enhances dopamine agonist effects.7 Kornfeld et al 6 have suggested and confirmed that the dopaminergic activity of ergoline derivatives is attributable to the moiety of the rigid pyrroloethylamine included in the ergoline structure as shown in 1.…”

mentioning

confidence: 99%

Synthesis and dopaminergic activity of trans-6-methyl-7a,8,9,10,11,11a-hexahydro-7H-pyrrolo[3,2,1-gh]-4,7-phenanthroline and trans-1,2,3,4,4a,5,6,10b-octahydro-4,7-phenanthroline derivatives

Claudi¹,

Cristalli²,

Martelli³

et al. 1986

The synthesis and dopamine agonist activity of some derivatives of trans-6-methyl-7a,8,9,10,11,11a-hexahydro-7H-pyrrolo[3,2,1-gh]- 4,7-phenanthroline (6a-c) are reported. These compounds can be regarded as analogues of ergoline derivatives with the indole nucleus replaced by indolizine. These congeners have been evaluated as inhibitors of prolactin release in vivo. trans-6-Methyl-8-ethyl-7a,8,9,10,11,11a-hexahydro-7H-pyrrolo[3,2,1-gh]- 4,7-phenanthroline (6b) proved to produce a dose-dependent inhibition of serum prolactin that was almost complete at the highest dose employed. Although effective, this compound was far less potent than bromocriptine. The 8-propyl derivative 6c was weakly active only at very high doses, and the 8-methyl derivative 6a proved to be completely ineffective. trans-4-Propyl-1,2,3,4,4a,5,6,10b-octahydro-4,7-phenanthroline (7), a molecular simplification of hexahydropyrrolo-4,7-phenanthroline, proved to be the most potent among the newly synthesized compounds. These results, taken together with those of previous studies, suggest that the presence of the nitrogen of the indolizine nucleus and the N-7 in the octahydro-4,7-phenanthroline 7 are significant for the interaction with the dopamine receptor involved in the control of prolactin release.