Synthesis and in vitro structure-activity relationship of 13-tert-butyl-ergoline derivatives as 5-HT1A receptor ligands (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.
Ergoline Derivatives as a Probe for Featuring the 5-HT 1A Receptor Pharmacophore
Journal of Molecular Modeling, 1995
A 5-HT 1A pharmacophore has been obtained employing a set of rigid templates encompassing the 5-HT structure. The use of rigid templates allowed us to overcome the discrepancy found when flexible structures where the energy of the active conformers are sometimes higher than the global minimum energy are used. On the basis of the results herein reported the three-dimensional requirements necessary for the binding interaction have been defined within this set of molecules. In this study forbidden zones of the receptor have been characterised. The pharmacophore model derived places some agonist/antagonist pharmacophore models appeared in the literature in question.
European Journal of Medicinal Chemistry, 1999
A series of (3,5-dioxopiperazin-1-yl)ergoline derivatives has been synthesised and evaluated in vitro and in vivo for their dopaminergic D 1 and D 2 components. The structural contributions to the pharmacological profile of the ergoline skeleton, its substituents on positions 1, 2, 6, 9, and the 3,5-dioxopiperazin-1-yl portion of the molecule were examined. Structure-activity relationships within this series suggested that substitution on the ergoline skeleton in position 1 or 2 and on the 3,5-dioxopiperazin-4-nitrogen generated compounds with a spectrum of dopamine agonistic/antagonistic activity sensitive to both the nature and position of substituents. © Elsevier, Paris ergoline derivatives / structure-affinity relationship / dopaminergic / antidopaminergic activity
European Journal of Pharmacology, 1993
Previous studies indicated that selected ergolines and tryptamines showed species differences for affinity to the antagonist-labeled 5-HT2 receptor. The present study examined these same compounds for affinity at the agonist-labeled 5-HT2 receptor in rat and squirrel monkey cortical homogenates using [125I]DOI ([125I]1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane). As seen with the antagonist-labeled 5-HT2 receptor, N(1) alkyl substitution of either the ergolines or tryptamines resulted in a slight increase or no effect on their affinity for the agonist-labeled rat 5-HT2 receptor. In contrast, these same N(1) substitutions resulted in significant decreases in affinity for the agonist-labeled monkey 5-HT2 receptor. It was also noted that N(1)-unsubstituted ergolines and tryptamines (such as ergonovine, LY86057, LY193525 and 5-methoxytryptamine) tended to have higher affinity for the monkey versus the rat agonist-labeled receptor. However, the N(1) alkyl-substituted ergolines and tryptamines (such as mesulergine, LY53857, amesergide, N(1)-isopropyltryptamine and N(1)-isopropyl-5-methoxytryptamine) showed significantly lower affinity for the monkey versus the rat 5-HT2 receptor. These data suggest that, at least in relation to the N(1) position, ergolines and tryptamines bind in a similar orientation. These results are also discussed in terms of what amino acid differences between species may account for this structure-activity relationship.
Pharmacology Biochemistry and Behavior, 1994
KRISCH, I. AND B. BOLE-VUNDUK. Behavioral studies on LEK-8804, a new ergofine derivative with potent 5-HTIA receptor agonist and 5-HT2 receptor antagonist activity. PHARMACOL BIOCHEM BEHAV 47(2) [301][302][303][304][305] 1994.-The 5-HTLA receptor-mediated tall flick response in rats and the 5-HT2 receptor-mediated head twitch response in mice were used to study the functional activity of a new ergoline derivative, 9,10-didehydro-N-(2-propynyl)-6-methylergoline-8/~-carboxamide (LEK-8804). LEK-8804 dose-dependently elicited spontaneous tail flicks in rats, indicating a full 5-hydroxytryptamine~^ (5-HT~,0 agonist activity. This effect was very similar to that produced by the selective 5-HTtA agonist 8-OH-DPAT, both in terms of potency and time-effect relationship, and was blocked by the selective 5-HT~A antagonist . In contrast, LEK-8804 by itself failed to produce head twitches in mice but dose-dependently inhibited the 5-hydroxytryptophan (5-HTP)induced behavior. The inhibitory effect of LEK-S804 upon 5-HTP-induced head twitches was not attenuated by the selective 5-HT~A antagonist . This indicates that probably not the agonist action on 5-HT1A receptors but instead the antagonism on 5-HT2 receptors was involved in the inhibition of head twitch response. It is suggested that LEK-8804 is a potent full 5-HT~A receptor agonist with possible 5-HT2 receptor antagonist properties.
Design, synthesis and binding properties of novel and selective 5-HT3 and 5-HT4 receptor ligands
European Journal of Medicinal Chemistry, 2000
This work reports the synthesis and the binding tests on the 5-HT 3 and 5-HT 4 receptors of new thienopyrimidopiperazine and piperazinylacylaminodimethylthiophene derivatives, in order to identify potent and selective ligands for each receptor. The 3-amino-2-(4-benzyl-1-piperazinyl)-5,6-dimethyl-thieno[2,3-d]pyrimidin-4(3H)-one derivative 28 showed the highest affinity and selectivity for the 5-HT 3 over the 5-HT 4 receptor (5-HT 3 K i = 3.92 nM, 5-HT 4 not active), whereas the 2-[4-[4-(2-pyrimidinyl)-1piperazinyl]butanoylamino]-4,5-dimethyl-3-thiophenecarboxylic acid ethyl ester showed the highest affinity and selectivity for the 5-HT 4 over the 5-HT 3 receptor (5-HT 4 K i =81.3 nM, 5-HT 3 not active). Conformational analyses were carried out on the compounds of the piperazinylacylaminodimethylthiophene series (39-42) taking compound 41 as the template. © 2001 É ditions scientifiques et médicales Elsevier SAS
Journal of Medicinal Chemistry, 1999
Novel 5-HT 3 receptor ligands were designed and synthesized with the aim of obtaining deeper insight into the molecular basis of the intrinsic efficacy of arylpiperazines interacting with the central 5-HT 3 receptor. The newly synthesized compounds and some previously published compounds belonging to the same class of heteroarylpiperazines were tested for their potential ability to displace [ 3 H]granisetron from rat cortical membranes. These 5-HT 3 receptor binding studies revealed subnanomolar affinity in several of the compounds under study. The most active ligands were quipazine derivatives bearing a phenyl group in the 4-position and various oxygenated alkyl side chains in the 3-position of the quinoline nucleus. Qualitative and theoretical quantitative structure-affinity relationship studies were carried out, and the interaction model for the 5-HT 3 ligands related to quipazine with their receptor, proposed in part 1 of the present work, was updated to incorporate the latest data. The potential 5-HT 3 agonist/antagonist activity of 12 selected compounds was assessed in vitro on the 5-HT 3 receptordependent [ 14 C]guanidinium uptake in NG 108-15 cells. Their intrinsic efficacy ranged from the 5-HT 3 full agonist properties of compounds 7a and 8h,i to those of partial agonists 10a,d and antagonists 8b,d,e, and 9c,d,h,i. The comparison between these functional data and those relative to the previously described compounds suggested that in this class of 5-HT 3 ligands the intrinsic efficacy is modulated in a rather subtle manner by the steric features of the heteroaryl moiety.