Minamitake Y, Furuya M, Kitajima Y, Takehisa M, Tanaka S
Suntory Institute for Biomedical Research, Osaka, Japan.
Chem Pharm Bull (Tokyo). 1990 Jul;38(7):1920-6. doi: 10.1248/cpb.38.1920.
Conformationally restricted analogs of alpha-human atrial natriuretic peptide (alpha-hANP) containing L- or D-penicillamine, or D-cysteine in place of cysteine residues at positions 7 and 23 were synthesized by the liquid phase procedure. Their biological properties in the assays of receptor binding and cyclic guanosine monophosphate (cGMP) accumulation employing rat vascular smooth muscle cells (VSMC), vasorelaxant activity using rat isolated aorta were evaluated. We found that the constrained and/or stereochemically altered ring moiety generally did not influence the receptor binding activity, however, cGMP accumulation and vasorelaxant activities were quite sensitive to conformational perturbation. Furthermore, a lack of correlation between cGMP accumulation activity and vasorelaxant activity was observed. Dissociation between these activities was typical in the case of [DPen7,23]-alpha-hANP(7-28), which showed quite weak vasorelaxant activity in spite of its full cGMP accumulation and receptor binding potencies. This result suggests that cGMP accumulation alone is not sufficient to promote ANP-induced vasorelaxation, and that the other second messenger(s) may mediate this activity.
通过液相法合成了α-人心房利钠肽（α-hANP）的构象受限类似物，这些类似物在第7位和第23位用L-或D-青霉胺或D-半胱氨酸取代了半胱氨酸残基。利用大鼠血管平滑肌细胞（VSMC）评估了它们在受体结合和环磷酸鸟苷（cGMP）积累测定中的生物学特性，利用大鼠离体主动脉评估了它们的血管舒张活性。我们发现，受限和/或立体化学改变的环部分通常不影响受体结合活性，然而，cGMP积累和血管舒张活性对构象扰动相当敏感。此外，观察到cGMP积累活性和血管舒张活性之间缺乏相关性。在[DPen7,23]-α-hANP(7-28)的情况下，这些活性之间的解离是典型的，尽管它具有完全的cGMP积累和受体结合能力，但其血管舒张活性相当弱。这一结果表明，仅cGMP积累不足以促进ANP诱导的血管舒张，其他第二信使可能介导这种活性。
