New Selective and Potent 5-HT_1B/1DAntagonists:  Chemistry and Pharmacological Evaluation ofN-Piperazinylphenyl Biphenylcarboxamides and Biphenylsulfonamides

Abstract

A series of new analogues of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl] 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (1; GR127935) as potent and selective 5-HT(1B/1D) antagonists were synthesized and evaluated pharmacologically. Their receptor binding profiles were comparable to that of 1. The 1,3,4-oxadiazole isomer 2 and the 4'-aminocarbonyl and 4'-amidinyl analogues (9 and 10) of 1 had higher affinities at the rat 5-HT(1B) receptor (IC(50) = 0.93, 1. 3, and 0.5 nM, respectively) and calf 5-HT(1D) receptor (IC(50) = 37, 10, and 3 nM, respectively) than did 1 (1.6 and 52 nM for rat 5-HT(1B) and calf 5-HT(1D) receptors, respectively). In the functional in vitro testing of 5-HT(1B/1D) antagonistic properties, 2, 9, 10, 11b (O-demethylated derivative of 2), 13a (O-methylsulfonyl analogue of 2), and 16 (which differs from 2 with a sulfonamide linker) showed more pronounced effects in the K(+)-induced 5-HT release in the cortex of guinea pig than did 1 and 3 (SB224289). Compounds 2, 9, and 10 were equally potent as 1 in rabbit saphenous vein model (pA(2) > 9). A biochemical study of 2 with in vivo microdialysis in the rat brain showed that it is capable of augmenting citalopram (a selective serotonin reuptake inhibitor, SSRI) induced 5-HT release in rat ventral hippocampus, while preventing the decrease in acetylcholine release elicited by citalopram administration. The molecular structure of 2 was determined by single-crystal X-ray analysis. The log P and log D values of these compounds were calculated. This study contributes to the SAR study of N-piperazinylphenyl biphenylcarboxamides as selective and potent 5-HT(1B/1D) antagonists.

Pharmacology of serotonin and female sexual behavior

“…MBH infusion with the 5-HT 1B/1D receptor antagonist, GR 127935 N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3--yl)-1,1′-biphenyl-4-carboxamide hydrochloride (Liao et al, 2000), inhibited lordosis behavior in rats made sexually receptive with estradiol benzoate priming but was considerably less evident in rats hormonally primed with estradiol benzoate and progesterone (Uphouse et al, 2009). Interestingly, the effect of the 5-HT 1B/1D receptor antagonist appeared to result from an amplification of infusion stress on lordosis behavior (Uphouse et al, 2009).…”

In vivobrain microdialysis: advances in neuropsychopharmacology and drug discovery

“…The 5-HT 1A antagonist WAY-101405 increased ACh in rat hippocampus and concomitantly antagonized memory deficits in fear conditioning induced by scopolamine [142]. 5-HT 1B antagonists do not increase ACh levels by themselves, but they may be useful as a comedication to antidepressant 5-HT-selective re-uptake inhibitors (SSRIs) because SSRI treatment leads to a decline of ACh levels secondary to the increase of 5-HT levels [143]. The 5-HT 6 receptor has been the target of drug development in cognition, schizophrenia and obesity.…”

Synthesis of (E)-2-(arylbenzylidene)-2-((4-methoxyphenyl)amino) acetohydrazide derivatives and their antimicrobial activity

“…3 In particular, compounds bearing 1,3,4-oxadiazoles nucleus are known to have unique angioedema and anti-inflammatory activities. 4 Substituted oxadiazoles molecules possess other interesting properties such as analgesic 5 , antimicrobial 6 , antiviral 7 , anticonvulsant 8 , antihypertensive 9 , anti-proliferative 10 , enzyme Inhibitors 11 , 5-HT-receptor antagonists 12 and inhibitors of muscle glycogen phosphorylase 13 .…”