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In Vitro Pharmacology >> GPCRs >> Allosteric

Custom GPCR Services for Drug Discovery

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AllostericProfiler™ and AllostericScreener™ Services

Our GPCR experts, with extensive experience in both binding and functional assays, are available for custom GPCR projects to meet your specific drug discovery needs. We can create a novel GPCR assay including cell line development, modify an existing protocol, or transfer your existing GPCR assay(s) to run in our facility. GPCR high-throughput screens (HTS) may also be conducted in our laboratory to meet the demands of your drug discovery projects(s).

All custom GPCR projects have a dedicated PhD level scientist that will develop a detailed work plan with the client prior to the initiation of a project. During a project intermediate reports are available that include predetermined time points for Go/No-Go decisions.

Custom GPCR Binding Capabilities:

  • Binding kinetics ( kon / koff )
  • Binding reversibility
  • Allosteric modulation of binding
  • Assay development with client-specified radioligand(s) or cell line(s)
  • Optimization of assay parameters, including Kd determination

Custom Functional GPCR Capabilities:

  • Inverse agonism
  • Allosteric modulation (PAM/NAM)
  • Assay development with client-specific receptor/cell line, including non-human species
  • New assay with client-specified readout
  • Optimization of assay parameters, including agonist EC50 determination

Figure 1. Distinct interactions sites for allosteric compounds.

Represented are the theoretical binding sites for an orthosteric compound (A) and an allosteric compound (B). Orthosteric and allosteric compounds can simultaneously occupy distinct sites on a GPCR to modify the receptor's activity (C).


Figure 2. Sample of experimental data generated by an AllostericProfiler™ selectivity screen on a set of allosteric modulators against Class A, B and C GPCRs.

Shown are the resulting dose response curves generated during the second addition step, in which the reference agonist was added to cells that had been treated with10 μM (or 30 μM for CGP 7930 and CGP 13501) of the indicated test compounds during the first addition step. A) α2A adrenergic family receptor. 5-(N,N-hexamethylene) amiloride, a reported α2A NAM, was found to inhibit this Class A receptor as indicated by a rightward shift in epinephrine's dose response curve. B) M4 acetylcholine muscarinic family receptor. Two compounds, VU 0152099 and VU 10010, were both found to potentiate the response of this Class A receptor to its native ligand, acetylcholine, as indicated by a leftward shift in the curve. C) CRF1 corticotropin-releasing factor family receptor. This Class B receptor was inhibited by two different molecules, NBI 27914 and antalarmin, that were previously reported to be NAMs. This inhibition is demonstrated by either the rightward shift in urocortin's potency and/or decrease in its apparent efficacy, respectively. D) GABAB receptor. Both reported GABAB receptor PAMs, CGP 7930 and CGP 13501, were able to potentiate GABA's signaling as indicated by the observed increase of GABA's potency in the presence of these PAMs.