Unraveling the inhibitory mechanism of adenylyl cyclase 8E: New insights into regulatory pathways of cAMP signal integration.

Adenylyl Cyclase 8E (AC8E), which lacks part of M1 transmembrane domain, has been previously shown to dimerize with AC3 and down-regulate its activity, but the molecular mechanism of this inhibitory effect has remained elusive. Here, we first show that AC8E also inhibits AC2 and AC6, highlighting the functional importance of this novel regulatory mechanism in the cAMP signaling pathway across AC families. We then completed the partial structure of Bos taurus AC9 using combinations of comparative modeling and fold recognition methods, and used this as a template to build the first full 3D-models of AC8 and AC8E. These models evidenced that the lack of M1 transmembrane domain of AC8E shifts the N-terminal domain, which impacts the orientation of the helical domains, thus affecting the catalytic site. This was confirmed in living cells with cAMP imaging, where we showed that the N-terminal domain is required for reducing cAMP production. Our data also show that AC8E prevents the translocation of other ACs towards the plasma membrane, further reducing the cAMP responsiveness to extracellular signals. This newly discovered dual inhibitory mechanism provides an additional level of regulation of cAMP-dependent signals integration.

Synthesis of new pyrroles of potential anti-inflammatory activity.

We herein disclose a series of novel pyrrole derivatives 1-4 and pyrrolo[2,3-d]pyrimidine derivatives 6-11 as novel potent anti-inflammatory compounds. The structures were confirmed by IR, (1) H-NMR, and MS. Some newly synthesized compounds were examined for their in-vivo anti-inflammatory activity. Several derivatives showed a promising anti-inflammatory activity compared to ibuprofen. In this paper, we examine and discuss the structure-activity relationships and anti-inflammatory activities of these compounds.

Synthesis and evaluation of novel pyrroles and pyrrolopyrimidines as anti-hyperglycemic agents.

A series of pyrrole and pyrrolopyrimidine derivatives were examined for their in vivo antihyperglycemic activity. Compounds Ia-c,e, and IVg showed promising antihyperglycemic activity equivalent to a well-known standard antihyperglycemic drug, Glimepiride (Amaryl, 4 mg/kg). In this paper, we examine and discuss the structure-activity relationships and antihyperglycemic activity of these compounds.