I. History

The International Union of Basic and Clinical Pharmacology (IUPHAR) has a longstanding and formal collaboration with Pharmacological Reviews. NC-IUPHAR is the Nomenclature and Standards Committee of IUPHAR. The mission for NC-IUPHAR was initiated in 1987 at the Xth International Congress of Pharmacology. In 1989, the Executive Committee of IUPHAR initially appointed Paul Vanhoutte as Chairman of NC-IUPHAR. NC-IUPHAR has grown and consists of a core group of approximately 20 scientists and many international corresponding members. Corresponding members assist to broaden the core committee's expertise and increase NC-IUPHAR's global representation. The current committee is chaired by Stephen Alexander.

I have personally been involved with NC-IUPHAR since 2001 and have been the NC-IUPHAR editor for Pharmacological Reviews for the past 18 years. I have been the editor for approximately 50 IUPHAR Pharmacological Reviews papers. It has been an honor and privilege to be a part of IUPHAR and the editorial leadership at Pharmacological Reviews. It has also provided me the opportunity to be at the forefront of pharmacological research and drug development and continues to be an opportunity to watch pharmacology evolve in basic and clinical medicine.

NC-IUPHAR has several remits (https://iuphar.org/sections-subcoms/nc-iuphar/); however, the primary responsibility as it relates to Pharmacological Reviews is to facilitate the issuing and endorsing guidelines for pharmacological nomenclature and classification of all human biological targets. This includes all the targets of current and future prescription medicines. An additional remit of NC-IUPHAR is to foster innovative drug discovery, in which Pharmacological Reviews plays an important role. The official reports from NC-IUPHAR are published in Pharmacological Reviewsin a Roman numeral–numbered series. There are currently 115 (CXV) NC-IUPHAR publications in Pharmacological Reviews. I wonder if there is another biomedical society that has a series of authoritative publications at this number of sequential publications? The first NC-IUPHAR publications in Pharmacological Reviews occurred in 1992 (Kenakin et al., 1992; Spedding and Paoletti, 1992). The first Roman numeral–numbered publication of the IUPHAR series started in 1994 by Paul Vanhoutte and colleagues (Vanhoutte et al., 1994).

II. Growth of the Publications

In the early years, there was a major focus of activity on G protein–coupled receptors and efforts for a uniformly accepted nomenclature and classification. Many important and authoritative papers were published at this time, and the recommendations were generally accepted by the international pharmacology community. Guidelines for nomenclature of new receptor subtypes were initially published in Pharmacological Reviews (Vanhoutte et al., 1996).

Ensuing publications expanded from basic pharmacological nomenclature to new nomenclature and pharmacology concerning the actions of allosteric ligands (Christopoulos and Kenakin, 2002; Christopoulos et al., 2014) and ensuring the correct usage of receptor terminology (Neubig et al., 2003), including work on multiple receptor conformational states that may have different pharmacological properties (Kenakin, 1995).

In subsequent years, the focus expanded to other biological targets and pathways, including nuclear hormone receptors, ion channels, enzyme systems, transporters, immunopharmacology, malaria, COVID-19, and addressing other key issues in pharmacology. Pharmacological Reviews published unique and comprehensive compendia on nuclear hormone receptors and voltage-gated ion channels (Catterall et al., 2003; Catterall and Gutman, 2005; Germain et al., 2006; Laudet and Spedding, 2006). The articles in these compendia continue to be highly cited, valuable resources.

As NC-IUPHAR evolved, papers simply containing recommendations on the nomenclature of a receptor were no longer considered sufficient, so the objective was expanded to include the most up-to-date pharmacology and science. The objective was to be an authoritative source for all pharmacologists and the biomedical community. Interestingly, the early NC-IUPHAR publications were approximately 14 printed pages per article. More current NC-IUPHAR papers are approximately 75 printed pages, representing over a 400% increase in printed page number. This is likely attributable to the growth of the papers from basic nomenclature recommendation reports to authoritative and comprehensive reviews of the pharmacology and biology of the area of interest. This is the “brand” that was the intention for IUPHAR-endorsed papers. As Pharmacological Reviews has always had one of the highest impact factors in biomedical publishing, an IUPHAR-endorsed paper is considered most highly respected.

III. Science Impact Factors

In reviewing the 30+ year collaboration with Pharmacological Reviews, it becomes apparent that the NC-IUPHAR papers consistently rank as some of the most highly cited papers within the journal. Of the all-time top 20 most highly cited papers published in Pharmacological Reviews, NC-IUPHAR papers comprise 5 in the list. The papers include reviews on serotonin receptors, cannabinoid receptors, adenosine receptors, chemokine receptors, and angiotensin receptors. It is noteworthy that these papers go back to the 90s and continue to have robust citations with long citation half-lives (more than 10 years).

One of the most highly cited NC-IUPHAR articles in Pharmacological Reviews was the paper on serotonin receptors by Hoyer et al. (1994). This paper has nearly 4000 citations and is in the top 10 most highly cited papers in all Pharmacological Reviews. An update on serotonin receptors was published in the journal 30 years later by Barnes et al. (2021). It is noteworthy that the original Hoyer paper was one of the largest Pharmacological Reviews papers at the time, with 46 printed pages, whereas the recent serotonin update paper by Barnes et al. was 210 printed pages, a 350% increase in size from the original paper. This paper has the most printed pages ever published within Pharmacological Reviews. Indeed, although the update on serotonin receptors has only been published for approximately 3 years, it is already in the top 10 of the recent publications in Pharmacological Reviews.This paper will no doubt also be a future citation classic surpassing the original from 1994.

IV. Nomenclature Issues

As stated above, the remit for NC-IUPHAR has been to harmonize a consistent nomenclature within a field and between different laboratories to reduce confusion and allow for more accurate communication of scientific data and minimize discrepancies. Over the years, NC-IUPHAR has spent considerable time creating guidelines for standardized nomenclature. Although the composition of the NC-IUPHAR changed over time, two members who were committee members for decades, Michael Spedding and Sir Colin Dollery, provided consistency and thoughtful input into helping decide appropriate nomenclature and many other pharmacology-related matters over the years.

One of the initial Pharmacological Reviews publications of the standardization of receptor nomenclature and guidelines was adopted and published in 1998 (Humphrey and Barnard, 1998). It should be remembered that much of this work coincided with the human genome project. New genes were being discovered, and it was not always clear what to name them. And often, different receptor systems were called by different names, creating confusion in the literature. NC-IUPHAR was usually very effective in resolving nomenclature differences and developing consistent classifications. I can remember an NC-IUPHAR meeting discussing for several hours if a receptor should have a large “R” or a small “r” in its official nomenclature.

An example of receptor nomenclature disagreement within the literature occurred with the orexin/hypocretin receptors. At the time, the field was divided on the nomenclature used when publishing. NC-IUPHAR became involved in a resolution of the nomenclature discrepancy. NC-IUPHAR reviewed the situation and made the recommendation to harmonize the field and adopt orexin as the formal nomenclature Gotter et al. (2012). This receptor nomenclature of OX₁ and OX₂ has been largely adopted, and the issue was resolved.

NC-IUPHAR has been generally successful in this pursuit of nomenclature standardization; however, there have been several notable exceptions where there remain discrepancies in particular nomenclatures. For example, the FPR2/ALX receptor nomenclature has not yet been resolved. It became evident that similar agonist ligands could be recognized by the same receptor (Ye et al., 2009; Qin et al., 2022). NC-IUPHAR participated in trying to have different laboratories share reagents so that the respective research groups could test different ligands in their respective test systems. Ultimately, this did not prove achievable, and the differences remains. Despite the IUPHAR-endorsed publication of a nomenclature for these receptor systems, it has not been universally accepted. Researchers in their respective fields still hold on to the nomenclature that they believe is appropriate. This inability to resolve a nomenclature discrepancy illustrates one of the challenges for NC-IUPHAR. NC-IUPHAR is not the “pharmacology police.” Just because IUPHAR endorses a publication of what it believes is the most scientifically accurate and appropriate nomenclature, it cannot enforce its implementation.

Since the completion of the human genome project, there have been few surprises in terms of the discovery of novel genes encoding new receptors and other biological targets. But what remains is the orphan designation. The fact is that these receptors are considered orphans because the biological or pharmacological function is not known or the endogenous ligand has yet to be identified. This became a major focus for NC-IUPHAR and published several papers in Pharmacological Reviews on the validation of receptor deorphanization (Benoit et al., 2006; Kirby et al., 2010; Offermanns et al., 2011; Davenport et al., 2013; Vaudry et al., 2015; Kennedy and Davenport, 2018; Read et al., 2019).

Not all nomenclature updates necessarily warrant publication in Pharmacological Reviews. In situations like these, the online IUPHAR database, accessible via the IUPHAR website (https://www.iuphar-db.org) or the Guide to PHARMACOLOGY portal (https://www.guidetopharmacology.org), is updated with new nomenclature and pharmacology. Very often, the chairpersons of these target committees are authors of previous NC-IUPHAR Pharmacological Reviews papers.

V. Future and Conclusions

The history and present status of pharmacology research have been expertly published in Pharmacological Reviews. Pharmacological Reviews is the authoritative journal on the state-of-the art pharmacological therapeutics. Pharmacological Reviews will continue its tradition of publishing highly impactful articles. But what of the future? NC-IUPHAR and many other learned societies are currently looking at artificial intelligence (AI) for the future of medical therapeutics. Indeed, NC-IUPHAR currently has manuscripts in the Pharmacological Reviews near-term pipeline on AI in drug discovery. The impact of AI on the future of pharmacology basic research and drug discovery is eagerly anticipated.

It is interesting that the 75th anniversary of Pharmacological Reviews coincides within the same decade that the first edition of Goodman and Gilman’s The Pharmacological Basis of Therapeutics was published. We used to refer to Goodman and Gilman as the “blue bible.” Perhaps not surprising, the first editor of Pharmacological Reviews was Louis Goodman. This highlights an era where many scientists became interested in pharmacology, and the field grew markedly from this time. Many of the most important therapeutics were discovered and started to become available during this time. This is no doubt related to the dissemination of the new pharmacological science and supports that Pharmacological Reviews in collaboration with IUPHAR will make important future contributions to the advancement of modern medicines.