The multi-agonist era did not appear from nowhere. It is the latest chapter of a 120-year argument about what a receptor is — and how many of them one molecule should be allowed to touch. These are the names and the years.
John Newport Langley, studying how poisons act on muscle at Cambridge, concludes that drugs must bind a "receptive substance" on the cell (formalised in his 1905 paper in the Journal of Physiology). Paul Ehrlich reaches a parallel idea from immunology: cells carry side-chains that capture specific molecules — his "corpora non agunt nisi fixata" (bodies do not act unless bound). Neither man could see a receptor; both insisted it must exist.
Langley J.N., J. Physiol. 33, 374 (1905) · receptor history
Pharmacologist Raymond P. Ahlquist shows that adrenaline-like drugs produce two opposite patterns of effect and deduces two receptor types — alpha and beta adrenoceptors. It is the first crack in the "one drug, one effect" worldview: the same natural signal reads differently through different receptors. His 1948 paper was initially rejected by a major journal; it became one of the most cited in pharmacology.
Ahlquist R.P., Am. J. Physiol. 153, 586 (1948)
Robert Lefkowitz and Brian Kobilka isolate and clone the beta-2 adrenergic receptor and reveal the seven-helix architecture of the GPCR family — the largest class of drug targets in the genome. Kobilka's team later solves the first structure of a GPCR caught in the act of signalling. They share the 2012 Nobel Prize in Chemistry. Receptors were no longer a theory; they were engineering targets with atomic coordinates.
Nobel Prize in Chemistry 2012 · nobelprize.org
Richard Morphy and Zoran Rankovic (Organon) publish "Designed Multiple Ligands. An Emerging Drug Discovery Paradigm" — the formal case for engineering one molecule to hit several targets deliberately, rather than discovering such promiscuity by accident. The review becomes the reference point for everything now called polypharmacology.
Morphy R., Rankovic Z., J. Med. Chem. 48, 6523 (2005) · PubMed
Matthias Tschöp and Richard DiMarchi champion the peptide version of the idea: one engineered chain that co-activates gut-hormone receptors — GIP, GLP-1, glucagon — to treat metabolic disease as the network problem it is. Their collaboration with industry turns "how many receptors?" into a design dial rather than a side-effect.
Müller T.D., Blüher M., Tschöp M.H., DiMarchi R.D., Nat. Rev. Drug Discov. 21, 201 (2022) · review
Tirzepatide — a single peptide engaging GIP and GLP-1 receptors — beats semaglutide head-to-head in type 2 diabetes (SURPASS-2, Frías et al., NEJM 2021), then delivers up to ~20.9% mean weight loss in obesity (SURMOUNT-1, Jastreboff et al., NEJM 2022). The FDA approves it as Mounjaro (2022) and Zepbound (2023). Dual agonism leaves the journals and enters the pharmacy.
NEJM 385, 503 (2021) · NEJM 387, 205 (2022) · FDA, 2023
Retatrutide adds the glucagon receptor to the GIP/GLP-1 pair. Phase 2 (Jastreboff et al., NEJM 2023) reports up to ~24.2% mean weight reduction at 48 weeks; the first phase 3 readout, TRIUMPH-4 (announced December 2025), reports ~28.7% at 68 weeks in obesity with knee osteoarthritis, with more TRIUMPH results expected through 2026. Meanwhile mazdutide — a GLP-1/glucagon dual agonist developed by Eli Lilly and Innovent Biologics — gains approval in China in 2025. Three receptors is now the clinical frontier.
NEJM 389, 514 (2023) · PubMed · Lilly, 2025 · Innovent, 2025
Every entry above widened the answer to "how many receptors can one peptide serve?" Panacea Bio Chem's Poliagonist programme, led by Bogdan Dicoias, treats that question as open: an amino acid chain designed residue-by-residue to engage a chosen constellation of receptors. We publish the reasoning and the credited science — not sequences, not targets, not data. If the number sounds extreme, remember that three did too.
Design-stage programme · disclosure follows data