CHIMICA È. . . CULTURA
COLLANA DI STORIA, FONDAMENTI
E DIVULGAZIONE DELLA CHIMICA

Direttore
Vincenzo V
Università degli Studi della Basilicata
Comitato scientifico
Giovanni V
Istituto di Chimica dei Composti Organometallici, CNR
Vincenzo S
Università degli Studi di Firenze
Maurizio D’A
Università degli Studi della Basilicata
Stefano S
Università degli Studi della Basilicata
Luciano D’A
Università degli Studi della Basilicata
Gaetano G
Università degli Studi della Basilicata
CHIMICA È. . . CULTURA
COLLANA DI STORIA, FONDAMENTI
E DIVULGAZIONE DELLA CHIMICA
Il cielo stellato sopra di me, la legge morale dentro di me.
Immanuel K
La collana nasce con una vocazione dichiaratamente interdisciplinare:
la Chimica viene intesa come link di un network molto più ampio,
una scena nel grande affresco della cultura moderna.
Mentre è difficile sopravvalutare il ruolo della Chimica nella società
moderna per le sue infinite utili applicazioni, è facile sottovalutarne
le implicazioni culturali dal punto di vista concettuale, al di là dei
puri tecnicismi.
Quali sono i fondamenti culturali della Chimica: la ricchissima storia,
la visione della natura, il rapporto con le arti, la riflessione filosofica
e più in generale il contributo ad una società sostenibile? Tutti questi
aspetti e implicazioni sono i temi approfonditi dai volumi pubblicati
in questa collana.
Piero Angeli
Receptor Chemistry
at Camerino University
The Birth of a “School”
Copyright © MMXIV
ARACNE editrice int.le S.r.l.
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via Quarto Negroni, 
 Ariccia
() 
 ----
No part of this book may be reproduced
by print, photoprint, microfilm, microfiche, or any other means,
without publisher’s authorization.
Ist edition: December 
Contents

Defining a “School”

Chapter I
How the School of Receptor Chemistry was born in Camerino
at the start of the s

Chapter II
The state of medicinal chemistry in Italy and internationally
during the s

Chapter III
The Camerino Symposium series

Chapter IV
The Camerino diaspora

Chapter V
The hardcore

Chapter VI
The other Camerino groups

Conclusions

Biographical notes

References

Defining a “School”
The march of research is punctuated by various ‘Schools’, which
serve as points of reference to guide the scholar in tracing the thread
of scientific progress. There is no set definition of a School. One
person’s definition may include certain criteria that are shared by
other people’s definitions, while also highlighting peculiarities that
seem less important to other people. In the end, however, we can
all agree that a School is formed when a group of researchers, in
a specific time and place, produce new quality research which is
recognized by the national and international scientific community.

Chapter I
How the School of Receptor Chemistry
was born in Camerino at the start of the s
Fulvio Gualtieri graduates in Rome in  with Prof. Giordano
Giacomello. In , Gualtieri moves to the Institute of Organic and
Medicinal Chemistry at Camerino University, a small institution in
the Marches region. He is appointed External Teacher in Industrial
Organic Chemistry at the Faculty of Sciences.
In , he is named Assistant to the Chair of Organic Chemistry within the same Faculty. In , he moves to the Faculty of
Pharmacy at the same university as Ordinary Assistant to the Chair
of Pharmaceutical and Toxicological Chemistry. He remains in this
role until . In , during the  International Meeting of Therapeutic Chemistry in Lyon, he meets Prof. Bernard Belleau, who is
working in the fascinating world of receptors. That year, Gualtieri
Figure .. Fulvio Gualtieri and Bernard Belleau


Receptor Chemistry at Camerino University
spends six months with Belleau’s group at McGill University (Montreal, Canada). There, he synthesizes an adrenergic ligand marked
with  S. It’s love at first sight. In –, he presents abstracts at
five congresses [–]. This precedes the publication of his first paper on cholinergic receptors ‘A cyclopentane analog of muscarone’
in the prestigious Journal of Medicinal Chemistry (, , ) with
co–authors Mario Giannella, Maria Pigini, and Carlo Melchiorre[].
Giannella and Pigini have been Gualtieri’s co–workers since ,
and Melchiorre since , when he joined Camerino University to
replace Gualtieri during his experience in the United States.
Figure .. Mario Giannella and Maria Pigini (Nelly)
Figure .. Carlo Melchiorre and Piero Angeli
. The birth of the Receptor Chemistry School

With this paper’s publication, Gualtieri and co–workers introduce
themselves to the international “receptorology” scene. They thus
join the area of research into how the ether oxygen and the keto
group of muscarine and muscarone, two fundamental ligands of the
cholinergic receptor, affect activity. The following year, Piero Angeli
joins the group, as their research continues with the synthesis and
study of the biological activity of desetermuscarine and its isomers
allo–, epi– and epiallo–desetermuscarine [–]. This leads to a high
number of authoritative publications.
Chapter II
The state of medicinal chemistry in Italy
and internationally during the s
It’s useful to remember that, in the mid–s, the Italian Chemical Society has no medicinal chemistry section. Future medicinal
chemists belong to the Organic Chemistry section. The other sections are Electrochemistry, Analytical Chemistry, Mass Spectrometry, Industrial Chemistry, and Chemical Engineering. In several
universities, medicinal chemists work in the Institutes of Organic
Chemistry. Camerino University has an Institute of Medicinal and
Organic Chemistry, however, and some other universities do have
Institutes of Medicinal Chemistry. Most of these researchers are involved with the study of reaction mechanisms and with the syntheses
of molecules with potential pharmaceutical interest. One exception is
Prof. Pietro Pratesi, who has been at Pavia University since the s.
Pratesi studies the absolute configuration of the stereogenic center
of adrenaline and nor–adrenaline, to correlate the chemical–physical
properties of the sympathicomimetic amines with their biological
activity []
The th National Congress of the Italian Chemical Society (SCI)
is held in Santa Margherita di Pula in  []. Universities, CNR,
the Istituto Superiore di Sanità, and several pharmaceutical companies all participate. Fifty–eight Communications are presented in
the Organic Chemistry section. The only Communication on the
study of a receptor ligand is by Gualtieri, Angeli, Giannella, and
Melchiorre, ‘Analoghi carbociclici della muscarina: sintesi della epiallo–desetermuscarina’ []. The SCI’s th National Congress is held
in Merano in  [], with the same participants as the previous
meeting. The Sections of the SCI are now reorganized into ‘Divisions’. The Organic Chemistry Division, which still includes the
medicinal chemists, introduces  Communications. Just three Communications deal with the study of a receptor, specifically the cholinergic receptor. All three are presented by Gualtieri and co–workers


Receptor Chemistry at Camerino University
[–]. In , the Medicinal Chemistry Division of the SCI is finally
born, presided over by Prof. Antonio Da Settimo. Its First National
Conference is held in Pisa in December of that year []. Medicinal
chemists from all the Italian Faculties of Pharmacy present a total
of  Communications. Ten Communications deal with the study
of a receptor from the chemical, biochemical, and pharmacological points of view. Two of these are presented by Gualtieri’s group,
which has now grown to include Livio Brasili and Dario Giardinà
[, ]. The Italian groups who have now begun to enter the field
of receptor research are essentially the following: Aldo Balsamo,
Bruno Macchia, and Adriano Martinelli [–], who are all Pisans
‘playing for their home team’. Their group investigates the alpha–
and beta–adrenergic receptors through classical structure–activity
relationships and quantum mechanical studies. Antonio Da Settimo’s
group [] deals with drug–histamine receptor interaction through
the conformational study of cimetidine. Anthony Lucacchini’s group
[] applies the affinity chromatography technique to the study of a
membrane protein, as a likely benzodiazepines receptor. Vincenzo
Tortorella’s [] group in Bari begins studying the adrenergic system through some sympathicomimetic morpholine derivatives. In
, Pietro Pratesi moves from Pavia to Milan. There, he begins
studying acetylcholine analogs and the cholinergic system, dealing
in particular with the synthesis of the bethanechol, muscarone, and
muscarine enantiomers. He collaborates with colleagues who are
experienced in chemical synthesis (Carlo De Micheli, Luigi Villa,
and Vincenzo Ferri in Milan), in evaluating biological activity (Enzo
Grana in Pavia), and in correlative analysis (Carlo Silipo and Antonio
Vittoria in Naples), respectively [].
Internationally, during the s and s, the study of receptors
involves not only chemistry and pharmacology, but also biochemistry,
biophysics, physiology, and computer science. Computers are used to
study quantitative structure–activity relationships and, thus, receptor
maps. These computers also facilitate communication between the
various actors, leading to the rapid rationalization of their respective
results. A handful of texts published in the s report on the state
of the art in contemporary receptor research. For researchers at the
time, these texts are a secular Bible, without which it would not have
been possible to orient themselves. These texts include Advances in
Drug Research by R.F. F (), Neurotransmitter–Receptor Interactions by D.J. T (), Chemical Pharmacology of the Synapse
. Medicinal chemistry in Italy and in the world

by D.J. T and C.R. T (), and the Medicinal Chemistry
collection by E.J. A (–). They document the various
stages of our knowledge of the “biological entity” destined to interact
with a drug.
Receptor isolation and characterization are the result of new techniques, such as affinity chromatography and affinity labeling, which
are developed in these years. By identifying new selective ligands and
developing binding techniques, new concepts are produced, which
enrich theories about receptors and provide new answers to old
questions. This leads to the discovery of receptor subtypes in what
were previously defined as homogeneous systems. The two–state
receptor model proposed at the end of the s was based on the interactions of classical agonists and antagonists. In the s, however,
the concepts of inverse agonist and cooperativity would take shape,
leading to the ternary cubic model in which the receptor is present
in three different conformational states.
Receptor topography study, which is based on the structure–activity relationship studies conducted by medicinal chemists during the
s, provides only a crude, though valid, sketch of the active sites involved in drug–receptor interaction. The advent of recombinant DNA
technology in the s, however, would provide new knowledge of
a receptor’s amino acid sequence and, in particular, its site–directed
mutagenesis. Together with computer graphics, this would provide
valuable information about a receptor’s three–dimensional structure
and the amino acids involved in a given interaction.