TABLE 2.
Representative examples of biased allosteric modulation
CaSR, calcium-sensing receptor; Oxo, oxotremorine (1-(4-pyrrolidin-1-ylbut-2-yn-1-yl)pyrrolidin-2-one); Oxo-M, oxotremorine methiodide (N,N,N-trimethyl-4-(2-oxo-1-pyrolidinyl)-2-butyn-1-ammonium iodide); PLD, phospholipase D; TMA, tetramethylammonium.
| Ligand | Receptor | Bias profile (and orthosteric agonist probe) |
|---|---|---|
| Cinacalcet | CaSR | PAM for intracellular Ca2+ mobilization (Ca2++) |
| NAL for ERK1/2 phosphorylation (Ca2+) | ||
| LPI805 | Neurokinin 2 | NAM for cAMP production (Neurokinin A) |
| NAL for intracellular Ca2+ mobilization (Neurokinin A) | ||
| 2-amino-3-benzothiophene derivative (MIPS#?) | Adenosine A1 | Allosteric agonist for cAMP production |
| VU0029767 | M1 | PAM for intracellular Ca2+ mobilization (ACh) |
| NAL for PLD activation (ACh) | ||
| Weak PAM for PI hydrolysis (ACh) | ||
| LY203398 | M2 | PAM for ERK1/2 phosphorylation (ACh, Oxo, Oxo-M, TMA, or McN-343) |
| NAM for ERK1/2 phosphorylation (Pilocarpine or Xanomeline) | ||
| Brucine (mutant) | M3K7.32E | Allosteric PAM agonist for Gαq (CCh) |
| PAM for Gα12 (CCh) | ||
| NAL for Gαi (CCh) | ||
| 1-(4-Ethoxyphenyl)-5-methoxy-2-methylindole-3-carboxylic acid and Nα-tosyltryptophan | CTRH2 | NAMs for arrestin recruitment (prostaglandin D2) |
| NALs for G protein coupling | ||
| CPPHA | mGlu5 | PAM for intracellular Ca2+ mobilization (Glutamate or DHPG) |
| NAM for ERK1/2 phosphorylation (Glutamate or DHPG, low concentrations) | ||
| NAM for ERK1/2 phosphorylation (Glutamate or DHPG, high concentrations) | ||
| M-5MPEP | mGlu5 | NAM for intracellular Ca2+ mobilization (quisqualate or DHPG) |
| Weak NAM for PI hydrolysis (quisqualate or DHPG) | ||
| PDC113.824 | PGF2α | NAM for Gα12 (PGF2α) |
| PAM for Gαq (PGF2α) | ||
| ORG27569 | CB1 | NAM for Gαi (CP55940) |
| Allosteric agonist for ERK1/2 phosphorylation |