Agonist model analogues

Another interesting finding was that two structurally close analogues of (15a), namely compounds (15b) and (15c), showed marked species-related differences in activity they behaved as weak antagonists towards hTRPVl, and weak agonists towards rTRPVl [78]. This observation indicates that great caution should be taken when extrapolating TRPVl actions from animal models to humans ... 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

The in vivo properties of compounds (464), (466) and (468)-(470) relative to (382) were investigated in two animal models a CBi agonist-induced hypotension rat model and a CBi agonist-induced hypothermia mouse model. Shown to be only moderately active in the in vitro screens, thiazole (464) and triazole (466) analogues failed to demonstrate convincing oral activity. Compound (468) was active in the hypotension model but showed... 

In a series of tetrahydrobenzo[ ]thiophene analogues, we have identified novel selective dopamine D3 receptor agents, one of which displays a 100-fold selectivity over dopamine D2 receptors. These results provide information for the development of pharmacophoric models of the dopamine D2 and D3 receptor subtypes that can be used for the future development of selective agonists at these receptor subtypes. 

Shapiro, G., Floersheim, P, Boelsterli, J., Amstutz, R., Bolliger, G., Gammenthaler, H., Gmelin, G., Supavilai, P, Walkinshaw, M. Muscarinic activity of the thiolactone, lactam, lactol, and thiolactol analogues of pilocarpine and a hypothetical model for the binding of agonists to the mj receptor. J. Med. Chem. 1992, 35, 15-27. 

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