D1 Agonist and/or D2 antagonist dopamine receptor properties of a series of ergoline derivatives: a structure–activity study (original) (raw)
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Serotonergic ergoline derivatives
Bioorganic & Medicinal Chemistry Letters, 1998
Novel classes of 13-and 14-tertbutyl-ergoline derivatives were prepared, and characterised in vitro for their affmity for adrenergic, dopaminergic and serotonergic binding sites. This study particularly examines the importance of the presence and the position of the tert-butyl group in conferring either significant 5-HT~A or 5-HT2 affinity and selectivity respectively.
Synthesis and SAR study of a novel series of dopamine receptor agonists
Bioorganic & Medicinal Chemistry, 2014
The synthesis of a novel series of dopamine receptor agonists are described as well as their in vitro potency and efficacy on dopamine D 1 and D 2 receptors. This series was designed from pergolide and (4aR,10aR)-1propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinolin-6-ol (PHBQ) and resulted in the synthesis of (2R,4aR,10aR)-2-methylsulfanylmethyl-4-propyl-3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-b][1,4]oxazin-9-ol (compound 27), which has a D 1 and D 2 receptor profile similar to that of the most recently approved drug for Parkinson's disease, rotigotine.
European journal of …, 1997
A series of novel 13-tert-butyl-ergoline derivatives was prepared and evaluated for affinity to adrenergic, dopaminergic and serotonergic receptor sites. Selectivity for 5-HT,, receptors versus a,, a2, D,, DZ, and 5HT2 appears to be influenced by the presence of the tert-butyl moiety at position 13 of the ergoline skeleton. Some compounds within this series display nanomolar 5-HTIA affinity and hundred-fold selectivity versus the other receptors considered.
Molecules, 2021
N-phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted N-phenylpiperazine analogs were evaluated. Compound 6a was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound 6a was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound 6a ...
Journal of medicinal chemistry, 1989
The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 recep...
Journal of Medicinal Chemistry, 1986
The N-allyl derivative (SK&F 85174) of 6-chloro-2,3,4,5-tetrahydro-l-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-diol (SK&F 82526) not only retains the exceptional D-1 agonist potency of its parent but also displays reasonably potent D-2 agonist activity, as measured by a dopamine-sensitive adenylate cyclase test and a rabbit ear artery assay, respectively. Several additional N-substituted compounds were prepared to explore the D-2/D-1 agonist relationship. The N-methyl analogue retained good D-2 agonist potency, but this substitution converted D-1 agonist activity into antagonist activity. Most other N-substituents sharply decreased D-2 agonist potency including the N-n-propyl group. This observation was surprising since the introduction of mono-or di-N-n-propyl substituent(s) is commonly linked with retention or enhancement of D-2 agonist potency in other series of dopamine agonists. The N-(2hydroxyethyl) analogue retains about one-fourth the D-2 potency of SK&F 85174. Several synthetic methods were used to prepare these compounds. N-Allylation of a trimethoxybenzazepine followed by cleavage of the methyl ethers with boron tribromide wa4 the preferred method. Other methods used were direct alkylation of the trihydroxy secondary amine, i.e., SK&F 82526, and an acylation-amide reduction-cleavage method.
Journal of Medicinal Chemistry, 1997
In an effort to define further the active geometry of the-phenyldopamine pharmacophore of certain dopamine D1 agonists, the title compounds have been synthesized as conformationally restricted homologues of the potent benzophenanthridine dopamine D1 agonist dihydrexidine 4a. The dihydroxy secondary amine 5b was evaluated as a potential agonist, whereas the N-methyl compounds 5a and 5c were hypothesized to be antagonists. Surprisingly, none of the three compounds had high affinity for dopamine D1 or D2 receptors. A comparison of the low-energy conformations of these molecules shows that the pendant phenyl ring of 5b is twisted about 28°relative to that of the corresponding ring of 4a. Further, the additional methylene used to expand the C ring of 5b projects toward the R face of the molecule, perhaps suggesting that steric protrusion in this region of the molecule is not tolerated. Finally, the phenethylamine fragment incorporated into these molecules deviates about 30°from the antiperiplanar conformation postulated to be necessary for agonist activity. On the other hand, the potential antagonist molecules 5a and 5c were compared with the dopamine D1 antagonist SCH 39166 2. The conformations of the former two structures differ quite dramatically from that of 2. The most notable differences lie in the relative orientations of the pendant phenyl rings in the two series, as well as the fact that the ethylamine fragment in 2 approximates a gauche conformation, while the comparable orientation in 5a and 5c more nearly approaches an antiperiplanar conformation. These findings will be used to refine further the model of the dopamine D1 agonist receptor that we have previously developed.