2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats.
Pan. Kevin K; Scott. Malcolm K MK; Lee. Daniel H S DH; Fitzpatrick. Louis J LJ; Crooke. Jeffery J JJ; Rivero. Ralph A RA; Rosenthal. Daniel I DI; Vaidya. Anil H AH; Zhao. Boyu B; Reitz. Allen B AB
Key Findings
- The new compounds bind the MC4 receptor with nanomolar potency (down to 4.4 nM).
- Injecting these compounds into rats sharply reduced food intake in a fasting‑induced feeding test.
- Oral administration was ineffective because the compounds are rapidly metabolized into inactive forms.
Practical Outcomes
- At present there’s no actionable protocol for humans—these molecules need injection and aren’t stable enough for oral use. More work on formulation or analogues would be required before biohackers could consider them for appetite control or longevity purposes.
Summary
Scientists made new chemicals that strongly activate the MC4 receptor, which can curb appetite in rats when injected, but they break down quickly if taken by mouth, so they aren’t useful for everyday self‑experiments yet.
Abstract
The melanocortin-4 receptor (MC4) modulates physiological functions such as feeding behavior, nerve regeneration, and drug addiction. Using a high throughput screen based on (125)I-NDP-MSH binding to the human MC4 receptor, we discovered 2,3-diaryl-5-anilino[1,2,4]thiadiazoles 3 as potent and selective MC4 receptor agonists. Through SAR development on the three attached aryl rings, we improved the binding affinity from 174 nM to 4.4 nM IC(50). When delivered intraperitoneally, compounds 3a, 3b, and 3c induced significant inhibition of food intake in a fasting-induced feeding model in rats. When delivered orally, these compounds lost activity, mainly due to rapid metabolism to inactive imidoylthiourea reduction products.
Study Information
pubmed
2003
2003-01-17T00:00:00.000Z
10.1016/s0968-0896(02)00428-5