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On his canvas entitled 'La trahison des Images' ('The Perfidy of Images'), Rene Magritte painted a tobacco pipe in a very realistic manner and added the words: 'Ceci n'est pas une pipe' ('This is not a pipe'). In similar style, it is of prime importance to state that the first three-dimensional (3D) models of G protein-coupled receptors (GPCRs) that have been defined and displayed are definitely not GPCRs and never will be. However, they probably represent a very important breakthrough in our understanding of GPCR structure and function as well as being a source of novel working hypotheses that can be experimentally explored. Several generations of scientists have elaborated their research on the concept of hormone-receptor interaction without having access to any structural representation of this molecular complex. Thus, for many years receptors remained only indirectly characterized through their functions or their binding properties. As a consequence, a number of important issues are still to be addressed. How does a hormone bind and activate its receptor? How does an antagonist inactivate a receptor? What is a partial agonist? What are the molecular mechanisms of signal transduction and modulation? Obviously, answers to these questions are of prime importance for medicinal chemists in their attempts to rationalize drug design.

Radioligand binding studies were performed in membranes of rabbit whole brain and striatum using the novel iodinated radioligand for 5-hydroxytryptamine 5-HT and 5-HT sites, Serotonin-5-O-Carboxymethyl-Glycyl[I]Tyrosinamide ([I]GTI). [I]GTI labelled a finite number of high affinity sites in rabbit brain membranes, B = 191 +- 47 fmol/mg protein, pK (-log mol/1) = 8.50 +- 0.13, n = 5. The pharmacological profile of [I]GTI binding was fully comparable to that reported previously in human and other brain preparations known to possess 5-HT sites (using either [H]5-HT or [I]GTI) and displayed a characteristic rank order of affinity: 5-carboxamidotryptamine > 5-HT = dihydroergotamine _> ergotamine ≥_ sumatriptan >_ CGS 12066 >- metergoline > yohimbine >_ methysergide > ICYP > 8-OH-DPAT >_ CP 93129 > (-)pindolol > ketanserin > isamoltane > mesulergine > corynanthine > buspirone > MDL 72222. Autoradiographic studies were performed on rabbit brain slices using [H]5-HT in the presence of 100 nmol/1 8-OH-DPAT and mesulergine (in order to mask 5-HT and 5-HT binding sites) and [I]CYP (iodocyanopindolol) in the presence of β µmol/I isoprenaline and 100 nmol/l 8-OH-DPAT (in order to mask β adrenoceptor and 5-HT binding sites). There was no detectable specific binding of [I]CYP through the brain, thus excluding the presence of 5-HT sites in rabbit brain. By contrast, [H]5-HT labelled a high density of sites in globus pallidus, substantia nigra and superior colliculus. Other regions displaying labelling include the striatum, the dentate gyrus of the hippocampus and the periaqueductal grey matter. This pattern of distribution is compatible with that reported for 5-HT sites in other species. The present data strongly suggest that rabbit brain has recognition sites with the pharmacological profile and distribution characteristic of the 5-HT recognition site. These findings are in agreement with results obtained by Limberger et al. (1991), suggesting the terminal 5-HT autoreceptor of the rabbit brain to belong to the 5-HT subtype. Except for limited species variations (see Bruinvels et al. 1992), the pharmacology of these sites does not justify an addition to the existing nomenclature ('5-HT'), in contrast to what has been proposed by Xiong and Nelson (1989). The rabbit represents another laboratory species in which 5-HT receptor mediated effects could be studied. [ABSTRACT FROM AUTHOR]