Synthesis of 2-phenyl-5,6,7,8-tetrahydroquinoxaline derivatives and screening for P2X1-purinoreceptor antagonist activity in isolated preparations of rat vas deferens, for translation into a male contraceptive.

Synthesis of 2-phenyl-5,6,7,8-tetrahydroquinoxaline derivatives and screening for P2X1-purinoreceptor antagonist activity in isolated preparations of rat vas deferens, for translation into a male contraceptive. Biol Reprod. 2020 Jul 10;: Authors: Mathiew M, Dennis B, Bennetts F, Su E, Nguyen N, Botteon A, Baell J, Ventura S Abstract Sympathetically mediated contractions of smooth muscle cells in vasa deferentia are mediated by neuronally released adenosine 5'-triphosphate (ATP) and noradrenaline, which stimulate P2X1-purinoreceptors and α1A-adrenoceptors respectively. This process is crucial for sperm transport, as demonstrated in knockout mouse studies where simultaneous genetic deletion of P2X1-purinoreceptors and α1A-adrenoceptors resulted in male infertility. We hypothesise that dual pharmacological antagonism of these two receptors could inhibit sperm transport sufficiently to provide a novel non-hormonal method of male contraception. To generate a suitable P2X1-purinoceptor antagonist, substituents were introduced on the phenyl moiety of 2-phenyl-5,6,7,8-tetrahydroquinoxaline to create a series of analogues that were tested for P2X1-purinoreceptor antagonism in isolated preparations of rat vas deferens. Novel compounds were initially screened for their ability to attenuate contractile responses to electrical field stimulation (EFS: 60 V, 0.5 ms, 0.2 Hz). The addition of polar substituents to the meta, but not ortho, positi...
Source: Biology of Reproduction - Category: Reproduction Medicine Authors: Tags: Biol Reprod Source Type: research