Possibility of auto receptor selective inverse agonists?

[dopamimetic]

So drugs targeting auto receptors like clonidine (an agonist, there is that clonidine suppression test suggesting that a single 300mcg administration causes NE levels to fall by >60% ) can be very efficient, and with reuptake inhibitors it is said that auto receptors are strong limiting factors until they (along with other receptors of course) downregulate. Some antipsychotics seem to cause an increase in dopaminergic transmission with low doses like ami/sulpride also due to auto receptor antagonism, but they are not that selective.

If we had drugs selective for auto receptors, could such ones with inverse agonist (or negative allosteric modulative, if possible) properties make new stimulants, painkillers or immediately-acting antidepressants?

 

[endotropic]

That was the idea with mixed 5-HT1A antagonists/SSRI's, but nothing really came of it. The neurogenesis theory for antidepressant action came into vogue when that combo didn't produce the expected effects.

 

[nAON]

I think one problem may be that autoreceptors aren't particularly selective for either excitatory or inhibitory output, and that their function is defined by the specific neural location they're found at more than anything - that it wasn't necessary for them to differentiate further [and be more targetable by systemic pharmacology], as they evolved as a fairly non-selective mechanism to limit neurotransmitter release that was happening right in front of them.

 

[Nagelfar]

Perhaps they will discover a substrate type pathway mechanism similar to the BBB that can loosely partition drug entry to keep drugs of specific molecular composition routed to one area of the brain more than another.