Behavioral studies on LEK-8804, a new ergoline derivative with potent 5-HT1A receptor agonist and 5-HT2 receptor antagonist activity

Krisch, Igor; Bole-Vunduk, Breda

doi:10.1016/0091-3057(94)90014-0

Cited by 6 publications

(2 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Drug discovery efforts in this area have focused on agents with serotonergic activity, because of considerable research indicating their potential for anxiolytic and antidepressant , activity. In particular, the focus of these efforts has been on combining 5-HT 1A and 5-HT 2 serotonin receptor activities which has led to the identification and characterization of WY-50,324 (SEB-324, adatanserin, 9 ), CGS 18102 A, S14761, FG 5893, LEK 8804, and BIM-17 (flibanserin) . While the previous agents are generally agonists or partial agonists at the 5-HT 1A receptor and antagonists at the 5-HT 2A/C receptor, a recent publication discloses selective 5-HT 1A and 5-HT 2A antagonists with potential anxiolytic activity …”

Section: Introductionmentioning

confidence: 99%

Synthesis and SAR of Adatanserin: Novel Adamantyl Aryl- and Heteroarylpiperazines with Dual Serotonin 5-HT_1A and 5-HT₂ Activity as Potential Anxiolytic and Antidepressant Agents

et al. 1999

View full text Add to dashboard Cite

Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.

show abstract

Section: Introductionmentioning

confidence: 99%

Synthesis and SAR of Adatanserin: Novel Adamantyl Aryl- and Heteroarylpiperazines with Dual Serotonin 5-HT_1A and 5-HT₂ Activity as Potential Anxiolytic and Antidepressant Agents

et al. 1999

View full text Add to dashboard Cite

show abstract

“…Many of them are DA D 2 receptor agonists, 23,24 but some ergoline derivatives also interact with serotonin receptors [25][26][27] and adrenoceptors 28,29 with very high affinities. Cabergoline is a selective D 2 agonist whereas apomorphine is a non-specific D 1 /D 2 agonist.…”

Section: Introductionmentioning

confidence: 99%

Salvage of sildenafil failures with cabergoline: a randomized, double-blind, placebo-controlled study

Safarinejad¹

2006

Int J Impot Res

View full text Add to dashboard Cite

To evaluate the safety and efficacy of cabergoline in men with erectile dysfunction (ED) who did not respond to sildenafil. Four hundred two sildenafil nonresponders aged from 21 to 59 years were included in the study. Patients were randomly divided into group 1, those who received 0.5-1 mg cabergoline weekly for 6 months and group 2, who received placebo for the same period. They underwent preliminary assessment, including medical and sexual history, self-administered International Index of Erectile Function (IIEF) and intravaginal ejaculatory latency time (IVELT) evaluation. Standard biochemistry and hematological laboratory tests, and measurement of serum testosterone and prolactin levels were also carried out. When indicated, other tests were used to establish the diagnosis of vasculogenic and neurogenic ED, including penile color duplex Doppler ultrasonography, pudendal nerve conduction test and impaired sensory-evoked potentials studies. The efficacy of two treatments was assessed every 2 weeks during treatment, at the end of the study, using responses to IIEF, IVELT evaluation, mean intercourse satisfaction domain, mean weekly coitus episodes and adverse drug effects. The trial was completed by 370 (92%) men. Positive clinical results were seen in 31.2% of patients in the cabergoline group compared with 7.1% of patients in the placebo group (P ¼ 0.04). The mean weekly intercourse episodes increased from pretreatment values of 1.4 and 1.2 to 2.2 and 1.4, for cabergoline and placebo, respectively (P ¼ 0.04). Baseline mean intercourse satisfaction domain values of IIEF 10 and 11 reached to 15 and 10 at 6-month treatment in groups 1 and 2, respectively (P ¼ 0.04). The IVELT after cabergoline and placebo gradually increased from 98 and 101 s to approximately 242 and 116 s, respectively (P ¼ 0.001). More drug-related adverse effects occurred in cabergoline group and 12 (5.9%) had to discontinue treatment (P ¼ 0.001). Cabergoline is moderately effective salvage therapy for sildenafil nonresponse. Further studies with different dosages and treatment regimens are necessary to draw final conclusions on the efficacy of this drug in ED.

show abstract

Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration

Ohgi

Futamura

Kikuchi

et al. 2013

Pharmacology Biochemistry and Behavior

184

120

View full text Add to dashboard Cite

Behavioral studies on LEK-8804, a new ergoline derivative with potent 5-HT1A receptor agonist and 5-HT2 receptor antagonist activity

Cited by 6 publications

References 33 publications

Synthesis and SAR of Adatanserin: Novel Adamantyl Aryl- and Heteroarylpiperazines with Dual Serotonin 5-HT_1A and 5-HT₂ Activity as Potential Anxiolytic and Antidepressant Agents

Synthesis and SAR of Adatanserin: Novel Adamantyl Aryl- and Heteroarylpiperazines with Dual Serotonin 5-HT_1A and 5-HT₂ Activity as Potential Anxiolytic and Antidepressant Agents

Salvage of sildenafil failures with cabergoline: a randomized, double-blind, placebo-controlled study

Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration

Contact Info

Product

Resources

About

Behavioral studies on LEK-8804, a new ergoline derivative with potent 5-HT1A receptor agonist and 5-HT2 receptor antagonist activity

Cited by 6 publications

References 33 publications

Synthesis and SAR of Adatanserin: Novel Adamantyl Aryl- and Heteroarylpiperazines with Dual Serotonin 5-HT1A and 5-HT2 Activity as Potential Anxiolytic and Antidepressant Agents

Synthesis and SAR of Adatanserin: Novel Adamantyl Aryl- and Heteroarylpiperazines with Dual Serotonin 5-HT1A and 5-HT2 Activity as Potential Anxiolytic and Antidepressant Agents

Salvage of sildenafil failures with cabergoline: a randomized, double-blind, placebo-controlled study

Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration

Contact Info

Product

Resources

About

Synthesis and SAR of Adatanserin: Novel Adamantyl Aryl- and Heteroarylpiperazines with Dual Serotonin 5-HT_1A and 5-HT₂ Activity as Potential Anxiolytic and Antidepressant Agents

Synthesis and SAR of Adatanserin: Novel Adamantyl Aryl- and Heteroarylpiperazines with Dual Serotonin 5-HT_1A and 5-HT₂ Activity as Potential Anxiolytic and Antidepressant Agents