Library · Biology & lab methods

What Pharmacological Receptor Modulation got wrong, from 9 theses

Summary written by a model from the records below: The records analyze methodological and pharmacological challenges encountered during receptor modulator development and functional evaluation. Across these investigations, researchers identified recurrent difficulties including unintended partial agonism, structural liabilities during ligand optimization, delivery limitations of unformulated agonists, and phenotypic decoupling from canonical receptor signaling. These records come from graduate theses, 2022 to 2026, each labeled with its degree where the repository states it, and each links to its thesis. They were extracted by language models reading the full text, so treat each as a lead to read, not a verdict.

9
theses
7
institutions
9
failure records
4
failure modes

Plus 4 problems the authors left open, listed at the end.

Failure modes, by theses reporting them

Select a mode to jump to its records.

Unintended partial agonism compromises antagonist or reference control utility
3
3 theses · 3 institutions · 3 records
Structural modifications and balance constraints impair ligand binding affinity
2
2 theses · 2 institutions · 2 records
Systemic delivery of unformulated free agonists fails to achieve in vivo antitumor efficacy
2
2 theses · 2 institutions · 2 records
Canonical receptor modulation uncouples from downstream phenotypic endpoints
2
2 theses · 2 institutions · 2 records

Unintended partial agonism compromises antagonist or reference control utility

3 theses · 3 institutions

Putative neutral antagonists exhibited intrinsic partial agonist activity that prevented transcriptional repression or in vivo pathway inhibition. Similarly, reference agonists such as dopamine showed apparent partial agonism and restricted response windows that impaired their utility as assay controls.

Tried and failed

neutral receptor antagonist treatment applied to constitutively active steroid receptor-dependent cancer. Outcome: no signal. Reason: exhibited partial agonist activity instead of repressing hormone-independent transcription

Characterization of the Foxa1-Glucocorticoid Receptor Complex As a Therapeutic Target in Non-Small Cell Lung Cancer · Cornell · PhD

Considered and rejected

Considered and rejected: Rejected using GIP28 as an in vivo GIPR antagonist after identifying partial agonist activity in dispersed islets and in vivo IPGTT

Investigating central and pancreatic GIPR signalling; implications for the treatment of metabolic disease · Imperial · Doctorate

Considered and rejected

Considered and rejected: Rejected using dopamine as the control agonist in favor of quinpirole due to dopamine displaying apparent partial agonism and a smaller response window at D3R.

An investigation into ligand selectivity between dopamine receptor subtypes, biased agonism, and protean agonism · Nottingham · Master's

Structural modifications and balance constraints impair ligand binding affinity

2 theses · 2 institutions

Scaffold modifications such as nitrogen methylation introduced steric hindrance that disrupted critical hydrogen bonding with receptor residues. In other optimization efforts, allosteric modulators failed to match the binding affinity of orthosteric baselines, and dual agonists suffered from an inability to balance independent receptor affinities.

Lost to a baseline

Lead NAM 40r EP2 binding affinity (Ki = 31 nM) was lower than orthosteric antagonists TG4-155 (Ki = 9.9 nM) and PF-04418948 (Ki = 16 nM).

Design, synthesis and characterisation of novel allosteric modulators for the prostaglandin EP 2 receptor · Nottingham · Doctorate

Considered and rejected

Considered and rejected: Decided against unimolecular dual GLP-1R/GCGR agonists (e.g. oxyntomodulin analogues) due to failure to optimize independent receptor binding and fixed ratio limitations

Monoagonist combinations for the treatment of obesity and diabetes, and the impact of biased signalling · Imperial · PhD

Systemic delivery of unformulated free agonists fails to achieve in vivo antitumor efficacy

2 theses · 2 institutions

Systemic administration of free small-molecule agonists resulted in insufficient tumor accumulation and immune activation to inhibit tumor growth. Although free agonists matched engineered drugamer formulations in generating peripheral antigen-specific T cells, they failed to produce comparable in vivo therapeutic antitumor responses.

Tried and failed

systemic administration of free small-molecule agonist applied to syngeneic colorectal carcinoma model. Outcome: no signal. Reason: free agonist lacked sufficient tumor accumulation or immune activation to inhibit tumor growth or improve survival

From Observation to Perturbation: Dissecting Cell State Transitions in Immune and Cancer Cells · MIT · PhD

Lost to a baseline

Free STING agonist treatment matched STING drugamers in inducing splenic antigen-specific CD8+ T cells but failed to improve therapeutic antitumor efficacy in vivo.

Synthetic Polymers To Address Multiscale Drug Delivery Challenges For Cancer Immunotherapy · University of Washington · PhD

Canonical receptor modulation uncouples from downstream phenotypic endpoints

2 theses · 2 institutions

Receptor antagonist cotreatment failed to prevent compound cytotoxicity because the underlying cell death proceeded through receptor-independent stress and apoptotic pathways. Likewise, substituting an endogenous ligand with a pan-agonist robustly induced target gene transcription but failed to translate into functional pathogen restriction.

Tried and failed

pharmacological receptor antagonist cotreatment to block toxicity applied to small-molecule induced cancer cell death. Outcome: no signal. Reason: Cytotoxicity proceeds through ER stress and apoptosis pathways independent of canonical receptor signaling.

LNS8801 INHIBITS ACUTE MYELOID LEUKEMIA · Penn · PhD

Considered and rejected

Considered and rejected: Rejected substituting ATRA with light-stable pan-RAR agonist TTNPB because TTNPB failed to elicit functional Mtb restriction despite robust target gene induction.

Improving and understanding macrophage restriction of Mycobacterium tuberculosis infection · Harvard · PhD

Left open by the authors

Problems the authors named and did not get to.

Left open

Meta-analyze published preclinical comparative studies evaluating DOR, MOR, and KOR agonists across analgesic efficacy and adverse effect profiles. Blocker: None

Delta Opioid Receptor Agonist Potential Use in Mitigating Opioid Withdrawal Symptoms · Harvard · Master's

Left open

Meta-analyze dose-response curves and administration routes of delta opioid receptor agonists across preclinical withdrawal assays. Blocker: None

Delta Opioid Receptor Agonist Potential Use in Mitigating Opioid Withdrawal Symptoms · Harvard · Master's

Left open

Collect functional efficacy data (EC50/Emax or agonist/antagonist classification) from pharmacological databases to refine candidate psychedelic receptor scoring. Blocker: None

Exploring Novel Psychedelic Treatments for Major Depression Through an Analysis of Key Receptor Sites · UT Austin

Left open

Optimize the in vitro functional assay resolution to distinguish between full and partial M3 muscarinic receptor agonists. Blocker: Requires wet-lab experimental pharmacology facilities and assay optimization protocols

Ligand-Induced Activation of the M3-Muscarinic Acetylcholine Receptor Liganden-induzierte Aktivierung des M3-muskarinischen Acetylcholinrezeptors · University of Marburg · PhD

Who has worked on this

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