Cycloalkanecarboxylic Esters Derived from Lysergol, Dihydrolysergol-I, and Elymoclavine as Partial Agonists and Antagonists at Rat 5-HT_2A Receptors:  Pharmacological Evidence that the Indolo[4,3-fg]quinoline System of the Ergolines Is Responsible for High 5-HT_2A Receptor Affinity

Abstract

Three series of cycloalkanecarboxylic esters derived from the naturally occurring clavine alkaloids lysergol, dihydrolysergol-I, and elymoclavine were synthesized to study their interaction with 5-HT2A receptors and alpha1-adrenoceptors in rat tail artery and aorta, respectively. Especially cycloalkanecarboxylic esters derived from lysergol showed complex behavior as partial agonists and antagonists of the contractile effect of 5-HT. Within this group, partial 5-HT2A receptor agonist activity was most potent for cyclopropanecarboxylic ester 6a (pKP = 7.67, alpha = 0.21) and decreased as the volume requirement of the alicyclic ring increased. This tendency was echoed in experiments where the compounds were used as antagonists of the contractile effect of 5-HT. From the structure-activity study, the N-1-isopropyl homologue of 6a, compound 6b, emerged as the ligand with the highest affinity for rat 5-HT2A receptors (pA2 = 8.74). For cycloalkanecarboxylic esters derived from dihydrolysergol-I and elymoclavine, no clear structure-affinity relationship could be deduced, although those compounds that had smaller cycloalkyl rings in the acyl portion and an isopropyl substituent at N-1 showed the highest 5-HT2A receptor affinity. On the other hand, cycloalkanecarboxylic esters derived from lysergol, dihydrolysergol-I, and elymoclavine displayed low or marginal affinity at alpha1-adrenoceptors. A further aim of the study was to examine to what extent the complete removal of the acyl portion of the esters would affect 5-HT2A receptor affinity. The parent alcohols of the three series of N-1-isopropyl homologues, 1-isopropyllysergol (1b), 1-isopropyldihydrolysergol-I (2b), and 1-isopropylelymoclavine (3b), displayed higher affinity for 5-HT2A receptors (pA2 = 9.15, 8.50, 9.14) than the corresponding esters. Compounds 1b-3b had no contractile effects by themselves and displayed low affinity at guinea-pig 5-HT1B receptors and rat alpha1-adrenoceptors. The high affinity for rat 5-HT2A receptors was retained when clavines even more simple in structure than 1b-3b, compounds 4b and 5b, were examined as 5-HT2A receptor antagonists. The nanomolar antagonist activity of simple clavines (1b-5b) in the rat suggests that the indolo[4,3-fg]quinoline system of the ergolines is the molecular fragment that is responsible for 5-HT2A receptor affinity, and not the substituent at position C-8.

Identification and validation of uterine stimulant methylergometrine as a potential inhibitor of caspase-1 activation

“…MEM (or methergine) is a synthetic analog of ergonovine, a psychedelic alkaloid found in ergot. It is a smooth muscle constrictor that functions via the antagonism of the dopamine D1 receptor which mostly acts on the uterus [ 33 , 34 ]. To this end, it is widely used in obstetrics to prevent or control excessive bleeding following childbirth and abortion.…”

Synthesis, Characterization and Evaluation of Anti-inflammatory and Analgesic Activity of Some Novel Quinoline Based Thiazolidinone Heterocycles

“…General procedure for the synthesis of (E)-2-(2arylidenehydrazinyl)quinoline (3)(4)(5)(6)(7)(8)(9) A mixture of compound 2 (1.0 g, 6.3 mmol) and the substituted aldehydes (6.3 mmol), were refluxed in ethanol (20 mL) containing few drops of glacial acetic acid for 3 h. The solvent was reduced to its half, and allowed to cool. The separated solid was filtered, dried, and recrystallized from ethanol.…”

“…The chemistry of quinoline derivatives has been of increasing interest due to their vast chemical reactivity, biological and pharmaceutical activities [1][2][3][4][5]. It has been reported that these derivatives possesses anti-tuberculosis [6,7], Antiplasmodial [4], Antibacterial [5], antihistamine [6], anticancer [11][12][13][14], anti-hypertensive [9], antifungal [10], antimalarial [11], anti-HIV [12] and antioxidant activities [13]. On the other hand, thiazole and thiazolidinone derivatives are known to exhibit diverse biological activities [14][15][16], they have anti-inflammatory [20,21], anticancer, antimicrobial [19], anti-tuberculosis [20] and antioxidant activity [21].…”

Physiologically active compounds interacting with serotonin (5-hydroxytryptamine) receptors

“…Thus, the ergoline structure of 5-HT 2 antagonists can in principle be reduced to a simple tetracyclic indoloquinoline system without any detriment to the affinity and antagonistic activity. 182 Other structural modifications of ergoline analogues included variations of substituents at the nitrogen atom of the indole moiety. It was shown that the introduction of small alkyl substituents, including branched ones, into this position is possible. }…”

“…In some cases, the antagonistic activity is enhanced due to the presence of a double bond in positions 9 and 10 present also in lysergic acid. 182 The literature data on the role of substituents in position 4 of the cyclohexane ring are controversial: in some cases, the methoxy group at C(4) of the cyclohexane ring significantly enhances the antagonistic activity, 187 but has no effect in other cases. 182 The majority of ergoline derivatives are active with respect to serotonin 5-HT 1 , adrenergic and other receptors, but are nonselective towards 5-HT 2 subtype receptors.…”