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5-HT3 Receptor

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Andrea Cappelli – One of the best experts on this subject based on the ideXlab platform.

  • Bivalent Ligands for the Serotonin 5-HT3 Receptor.
    ACS medicinal chemistry letters, 2011
    Co-Authors: Andrea Cappelli, Maurizio Anzini, Monica Manini, Marco Paolino, Andrea Gallelli, Laura Mennuni, Marta Del Cadia, Francesca De Rienzo, M. Cristina Menziani, Salvatore Vomero
    Abstract:

    The serotonin 5-HT3 Receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, can be considered to be an intriguing example of intrinsically multivalent biological Receptors. This paper describes a general design approach to the study of multivalency in this multimeric ion channel. Bivalent ligands for 5-HT3 Receptor have been designed by linking an arylpiperazine moiety to probes showing different functional features. Both homobivalent and heterobivalent ligands have shown 5-HT3 Receptor affinity in the nanomolar range, providing evidence for the viability of our design approach. Moreover, the high affinity shown by homobivalent ligands suggests that bivalency is a promising approach in 5-HT3 Receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 Receptor function.

  • novel potent 5 ht3 Receptor ligands based on the pyrrolidone structure synthesis biological evaluation and computational rationalization of the ligand Receptor interaction modalities
    Bioorganic & Medicinal Chemistry, 2002
    Co-Authors: Andrea Cappelli, Maurizio Anzini, Salvatore Vomero, Michel Hamon, Laura Mennuni, Francesco Makovec, E. Doucet, Cristina M Menziani, Pier G De Benedetti, Gianluca Giorgi
    Abstract:

    Abstract Novel conformationally constrained derivatives of classical 5-HT3 Receptor antagonists were designed and synthesized with the aim of probing the central 5-HT3 Receptor recognition site in a systematic way. The newly-synthesized compounds were tested for their potential ability to inhibit [3H]granisetron specific binding to 5-HT3 Receptor in rat cortical membranes. These studies revealed subnanomolar affinity in some of the compounds under study. The most potent ligand in this series was found to be quinuclidine derivative (S)-7i, which showed an affinity comparable with that of the reference ligand granisetron. The potential 5-HT3 agonist/antagonist activity of some selected compounds was assessed in vitro on the 5-HT3 Receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Both of the tropane derivatives tested in this functional assay (7a and 9a) showed antagonist properties, while the quinuclidine derivatives studied [the enantiomers of compounds 7i, 8g, and 9g, and compound (R)-8h] showed a full range of intrinsic efficacies. Therefore, the functional behavior of these 5-HT3 Receptor ligands appears to be affected by the structural features of both the azabicyclo moiety and the heteroaromatic portion. In agreement with the data obtained on NG 108-15 cells, investigations on the 5-HT3 Receptor-dependent Bezold–Jarisch reflex in urethane-anaesthetized rats confirmed the 5-HT3 Receptor antagonist properties of compounds 7a and (S)-7i showing for these compounds ID50 values of 2.8 and 181 μg/kg, respectively. Finally, compounds 7a, (S)-7i and 9a (at the doses of 0.01, 1.0, and 0.01 mg/kg ip, respectively) prevented scopolamine-induced amnesia in the mouse passive avoiavoidance test suggestive of a potential usefulness in cognitive disorders for these compounds. Qualitative and quantitative structure–affinity relationship studies were carried out by means of theoretical descriptors derived on a single structure and ad-hoc defined size and shape descriptors (indirect approach). The results showed to be useful in capturing information relevant to ligandReceptor interaction. Additional information derived by the analysis of the energy minimized 3-D structures of the ligandReceptor complexes (direct approach) suggested interesting mechanistic and methodological considerations on the binding mode multiplicity at the 5-HT3 Receptors and on the degree of tolerance allowed in the alignment of molecules for the indirect approach, respectively.

  • Novel potent and selective central 5-HT3 Receptor ligands provided with different intrinsic efficacy. 2. Molecular basis of the intrinsic efficacy of arylpiperazine derivatives at the central 5-HT3 Receptors
    Journal of medicinal chemistry, 1999
    Co-Authors: Andrea Cappelli, Maurizio Anzini, Salvatore Vomero, Michel Hamon, Laura Mennuni, Maria Cristina Menziani, Francesco Makovec, E. Doucet, Laura Canullo, Pier G De Benedetti
    Abstract:

    Novel 5-HT3 Receptor ligands were designed and synthesized with the aim of obtaining deeper insight into the molecular basis of the intrinsic efficacy of arylpiperazines interacting with the central 5-HT3 Receptor. The newly synthesized compounds and some previously published compounds belonging to the same class of heteroarylpiperazines were tested for their potential ability to displace [3H]granisetron from rat cortical membranes. These 5-HT3 Receptor binding studies revealed subnanomolar affinity in several of the compounds under study. The most active ligands were quipazine derivatives bearing a phenyl group in the 4-position and various oxygenated alkyl side chains in the 3-position of the quinoline nucleus. Qualitative and theoretical quantitative structure-affinity relationship studies were carried out, and the interaction model for the 5-HT3 ligands related to quipazine with their Receptor, proposed in part 1 of the present work, was updated to incorporate the latest data. The potential 5-HT3 agonist/antagonist activity of 12 selected compounds was assessed in vitro on the 5-HT3 Receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Their intrinsic efficacy ranged from the 5-HT3 full agonist properties of compounds 7a and 8h, i to those of partial agonists 10a,d and antagonists 8b,d,e, and 9c, d,h,i. The comparison between these functional data and those relative to the previously described compounds suggested that in this class of 5-HT3 ligands the intrinsic efficacy is modulated in a rather subtle manner by the steric features of the heteroaryl moiety.

Salvatore Vomero – One of the best experts on this subject based on the ideXlab platform.

  • Bivalent Ligands for the Serotonin 5-HT3 Receptor.
    ACS medicinal chemistry letters, 2011
    Co-Authors: Andrea Cappelli, Maurizio Anzini, Monica Manini, Marco Paolino, Andrea Gallelli, Laura Mennuni, Marta Del Cadia, Francesca De Rienzo, M. Cristina Menziani, Salvatore Vomero
    Abstract:

    The serotonin 5-HT3 Receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, can be considered to be an intriguing example of intrinsically multivalent biological Receptors. This paper describes a general design approach to the study of multivalency in this multimeric ion channel. Bivalent ligands for 5-HT3 Receptor have been designed by linking an arylpiperazine moiety to probes showing different functional features. Both homobivalent and heterobivalent ligands have shown 5-HT3 Receptor affinity in the nanomolar range, providing evidence for the viability of our design approach. Moreover, the high affinity shown by homobivalent ligands suggests that bivalency is a promising approach in 5-HT3 Receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 Receptor function.

  • novel potent 5 ht3 Receptor ligands based on the pyrrolidone structure synthesis biological evaluation and computational rationalization of the ligand Receptor interaction modalities
    Bioorganic & Medicinal Chemistry, 2002
    Co-Authors: Andrea Cappelli, Maurizio Anzini, Salvatore Vomero, Michel Hamon, Laura Mennuni, Francesco Makovec, E. Doucet, Cristina M Menziani, Pier G De Benedetti, Gianluca Giorgi
    Abstract:

    Abstract Novel conformationally constrained derivatives of classical 5-HT3 Receptor antagonists were designed and synthesized with the aim of probing the central 5-HT3 Receptor recognition site in a systematic way. The newly-synthesized compounds were tested for their potential ability to inhibit [3H]granisetron specific binding to 5-HT3 Receptor in rat cortical membranes. These studies revealed subnanomolar affinity in some of the compounds under study. The most potent ligand in this series was found to be quinuclidine derivative (S)-7i, which showed an affinity comparable with that of the reference ligand granisetron. The potential 5-HT3 agonist/antagonist activity of some selected compounds was assessed in vitro on the 5-HT3 Receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Both of the tropane derivatives tested in this functional assay (7a and 9a) showed antagonist properties, while the quinuclidine derivatives studied [the enantiomers of compounds 7i, 8g, and 9g, and compound (R)-8h] showed a full range of intrinsic efficacies. Therefore, the functional behavior of these 5-HT3 Receptor ligands appears to be affected by the structural features of both the azabicyclo moiety and the heteroaromatic portion. In agreement with the data obtained on NG 108-15 cells, investigations on the 5-HT3 Receptor-dependent Bezold–Jarisch reflex in urethane-anaesthetized rats confirmed the 5-HT3 Receptor antagonist properties of compounds 7a and (S)-7i showing for these compounds ID50 values of 2.8 and 181 μg/kg, respectively. Finally, compounds 7a, (S)-7i and 9a (at the doses of 0.01, 1.0, and 0.01 mg/kg ip, respectively) prevented scopolamine-induced amnesia in the mouse passive avoidance test suggestive of a potential usefulness in cognitive disorders for these compounds. Qualitative and quantitative structure–affinity relationship studies were carried out by means of theoretical descriptors derived on a single structure and ad-hoc defined size and shape descriptors (indirect approach). The results showed to be useful in capturing information relevant to ligand–Receptor interaction. Additional information derived by the analysis of the energy minimized 3-D structures of the ligand–Receptor complexes (direct approach) suggested interesting mechanistic and methodological considerations on the binding mode multiplicity at the 5-HT3 Receptors and on the degree of tolerance allowed in the alignment of molecules for the indirect approach, respectively.

  • Novel potent and selective central 5-HT3 Receptor ligands provided with different intrinsic efficacy. 2. Molecular basis of the intrinsic efficacy of arylpiperazine derivatives at the central 5-HT3 Receptors
    Journal of medicinal chemistry, 1999
    Co-Authors: Andrea Cappelli, Maurizio Anzini, Salvatore Vomero, Michel Hamon, Laura Mennuni, Maria Cristina Menziani, Francesco Makovec, E. Doucet, Laura Canullo, Pier G De Benedetti
    Abstract:

    Novel 5-HT3 Receptor ligands were designed and synthesized with the aim of obtaining deeper insight into the molecular basis of the intrinsic efficacy of arylpiperazines interacting with the central 5-HT3 Receptor. The newly synthesized compounds and some previously published compounds belonging to the same class of heteroarylpiperazines were tested for their potential ability to displace [3H]granisetron from rat cortical membranes. These 5-HT3 Receptor binding studies revealed subnanomolar affinity in several of the compounds under study. The most active ligands were quipazine derivatives bearing a phenyl group in the 4-position and various oxygenated alkyl side chains in the 3-position of the quinoline nucleus. Qualitative and theoretical quantitative structure-affinity relationship studies were carried out, and the interaction model for the 5-HT3 ligands related to quipazine with their Receptor, proposed in part 1 of the present work, was updated to incorporate the latest data. The potential 5-HT3 agonist/antagonist activity of 12 selected compounds was assessed in vitro on the 5-HT3 Receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Their intrinsic efficacy ranged from the 5-HT3 full agonist properties of compounds 7a and 8h, i to those of partial agonists 10a,d and antagonists 8b,d,e, and 9c, d,h,i. The comparison between these functional data and those relative to the previously described compounds suggested that in this class of 5-HT3 ligands the intrinsic efficacy is modulated in a rather subtle manner by the steric features of the heteroaryl moiety.

Shoichi Shimada – One of the best experts on this subject based on the ideXlab platform.

  • SR 57227A is a partial agonist/partial antagonist of 5-HT3 Receptor and inhibits subsequent 5-HT- or SR 57227A-induced 5-HT3 Receptor current.
    Biochemical and biophysical research communications, 2018
    Co-Authors: Yukiko Nakamura, Makoto Kondo, Yoshihisa Koyama, Shoichi Shimada
    Abstract:

    The serotonin (5-hydroxytryptamine) type 3 (5-HT3) Receptors are transmembrane ligand-gated ion channels. Although several 5-HT3 Receptor agonists have been used as preclinical tools, SR 57227A is the most commonly used 5-HT3 Receptor agonist with the ability to cross the blood brain barrier. However, the precise pharmacological profile of SR 57227A remains unclear. Therefore, we examined the pharmacological profile of SR 57227A at the 5-HT3A and 5-HT3AB Receptors. We microinjected Xenopus laevis oocytes with human 5-HT3A complementary RNA (cRNA) or a combination of human 5-HT3A and human 5-HT3AB cRNA and performed two electrode voltage clamclamp recordings of 5-HT3A and 5-HT3AB Receptor current in the presence of SR 57227A. Results showed that SR 57227A acts as partial agonagonist/partial antagonist at the 5-HT3 Receptor. Interestingly, SR 57227A specifically reduced subsequent current amplitudes induced by 5-HT or SR 57227A. Based on its 5-HT3 Receptor partial agonagonist/partial antagonist properties, we predict that SR 57227A functions as a serotonin stabilizer.

  • Direct modification of the 5-HT3 Receptor current by some anticancer drugs.
    European journal of pharmacology, 2017
    Co-Authors: Yukiko Nakamura, Makoto Kondo, Yusuke Ishida, Shoichi Shimada
    Abstract:

    The serotonin (5-hydroxytryptamine) type 3 (5-HT3) Receptor is an important target in the control of emesis, and 5-HT3 Receptor antagonists are effective against the early phase chemotherapy evoked vomiting. We recently reported that the anticancer drugs irinotecan and topotecan directly modulate the 5-HT-mediated 5-HT3 Receptor current in vitro. In addition, the drug response depends on the 5-HT3 subunit composition. Here, we explored the effects of 35 anticancer drugs on the 5-HT3 Receptor current. We microinjected Xenopus laevis oocytes with human 5-HT3A cRNA or a combination of human 5-HT3A and human 5-HT3B cRNA, and performed two-electrode voltage clamclamp recordings of 5-HT3A and 5-HT3AB Receptor currents in the presence of each of the 35 drugs. Over 25% of the drugs we tested inhibited or potentiated the 5-HT3 Receptor current. The drugs that modulated the 5-HT3 Receptor current had molecular weights of approximately 500. These results implied that these anticancer drugs could affect 5-HT3 Receptor.

  • Exercise-induced neuronal effects and the 5-HT3 Receptor
    Neurotransmitter, 2015
    Co-Authors: Makoto Kondo, Shoichi Shimada
    Abstract:

    Fourteen subtypes of the serotonin (5-hydroxytryptamine, 5-HT) Receptor have been delineated, and these subtypes are assigned to seven 5-HT Receptor subfamilies (5-HT1-7).  Among the 5-HT Receptor subfamilies, the 5-HT type 3 (5-HT3) Receptor is the only ionotropic Receptor. Previous studies have reported abundant expression of the 5-HT3 Receptor in the hippocampus, and the involvement in the mood and memory. However, possible roles of the 5-HT3 Receptor in hippocampal neurogenesis remains unknown. We performed immunohistochemical analyses of adult hippocampal neurogenesis in the 5-HT3A Receptor-deficient mice ( htr3a-/- mice). We found that basal cell proliferation and neurogenesis in the hippocampal dentate gyrus of htr3a-/- mice were normal. Exercise is known to increase hippocampal neurogenesis, cause antidepressant effects and enhance learning ability. Immunohistochemical and behavioral analyses of htr3a-/- mice revealed that a lack of the 5-HT3 Receptor led to a blockade of the exercise-induced neurogenesis in the hippocampus and antidepressant effects, but not of enhanced learning ability. Moreover, we have shown that the 5-HT3 Receptor agonist enhanced cell proliferation in the hippocampal dentate gyrus. Our results indicate that the 5-HT3 Receptor is indispensable for increased hippocampal neurogenesis and antidepressant effects induced by exercise.

Sarah C. R. Lummis – One of the best experts on this subject based on the ideXlab platform.

  • The 5-HT3 Receptor–the relationship between structure and function.
    Neuropharmacology, 2008
    Co-Authors: Nicholas M. Barnes, Sarah C. R. Lummis, Tim G. Hales, John A. Peters
    Abstract:

    The 5-hydroxytryptamine type-3 (5-HT3) Receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 Receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. Here, we review the relationship between the structure and the function of the 5-HT3 Receptor. 5-HT3A and 5-HT3B subunits are well established components of 5-HT3 Receptors but additional HTR3C, HTR3D and HTR3E genes expand the potential for molecular diversity within the family. Studies upon the relationship between subunit structure and the ionic selectivity and single channel conductances of 5-HT3 Receptors have identified a novel domain (the intracellular MA-stretch) that contributes to ion permeation and selectivity. Conventional and unnatural amino acid mutagenesis of the extracellular domain of the Receptor has revealed residues, within the principle (A-C) and complementary (D-F) loops, which are crucial to ligand binding. An area requiring much further investigation is the subunit composition of 5-HT3 Receptors that are endogenous to neurones, and their regional expression within the central nervous system. We conclude by describing recent studies that have identified numerous HTR3A and HTR3B gene polymorphisms that impact upon 5-HT3 Receptor function, or expression, and consider their relevance to (patho)physiology.

  • The 5-HT3 Receptor as a therapeutic target
    Expert opinion on therapeutic targets, 2007
    Co-Authors: Andrew J. Thompson, Sarah C. R. Lummis
    Abstract:

    The 5-HT3 Receptor is a neurotransmitter-gated ion channel. It is a member of the Cys-loop family of Receptors, which also includes nicotinic acetylcholine, glycine and GABAA Receptors. Each member of the family consists of an arrangement of five subunits surrounding a central ion-conducting pore. The 5-HT3 Receptor binding site is composed of six loops from two adjacent subunits, and the critical ligand binding residues within these loops are well documented. There are a range of 5-HT3 Receptor agonists and competitive antagonists, but it is the antagonists that dominate their clinical use. Studies have proposed a range of disease symptoms that might be amenable to 5-HT3 Receptor selective compounds; however, so far only the treatment of emesis and irritable bowel syndrome have been fully realised. In this review, the authors look at the structure, function and distribution of 5-HT3 Receptors and how this may influence their role in disease. The authors also describe the existing clinical applications of 5-HT3 antagonists and the future potential of these drugs.

  • Immunological characterization of 5-HT3 Receptor transmembrane topology.
    Journal of molecular neuroscience : MN, 2002
    Co-Authors: Avron D. Spier, Sarah C. R. Lummis
    Abstract:

    The 5-hydroxytryptamine3 (5-HT3) Receptor is a member of the Cys-loop family of ligand-gated ion channels. These Receptors are pentamers with the greatest homology to nicotinic acetylcholine (nACh) Receptors. The proposed topological organization of a 5-HT3 Receptor subunit is based largely on hydropathy profiles and by homology to nACh Receptors, and indicates a large N-terminal extracellular domain and four transmembrane regions. There is, however, little direct evidence for this model. We therefore investigated the topology of the 5-HT3A Receptor subunit using a panel of 5-HT3 Receptor-specific antisera that interact with defined regions of the Receptor. An antiserum generated against a short peptide from the N-terminal domain of the 5-HT3A Receptor subunit, pAb120, was shown to bind to 5-HT3 Receptor-expressing cells with intact cell membranes, indicating that the N-terminal end of the subunit is extracellular. Two antisera generated against regions of the loop between predicted transmembrane regions three and four did not bind to cells with intact membranes. However on membrane permeabilization these antibodies both bound to the Receptor in intracellular areas, thus indicating that the loop between transmembrane domains three and four is intracellular. These data therefore provide direct evidence for an extracellular N-terminal domain and an intracellular loop between the third and fourth transmembrane domains, thus supporting the conventional ligand-gated ion channel subunit topological model.

Maurizio Anzini – One of the best experts on this subject based on the ideXlab platform.

  • Bivalent Ligands for the Serotonin 5-HT3 Receptor.
    ACS medicinal chemistry letters, 2011
    Co-Authors: Andrea Cappelli, Maurizio Anzini, Monica Manini, Marco Paolino, Andrea Gallelli, Laura Mennuni, Marta Del Cadia, Francesca De Rienzo, M. Cristina Menziani, Salvatore Vomero
    Abstract:

    The serotonin 5-HT3 Receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, can be considered to be an intriguing example of intrinsically multivalent biological Receptors. This paper describes a general design approach to the study of multivalency in this multimeric ion channel. Bivalent ligands for 5-HT3 Receptor have been designed by linking an arylpiperazine moiety to probes showing different functional features. Both homobivalent and heterobivalent ligands have shown 5-HT3 Receptor affinity in the nanomolar range, providing evidence for the viability of our design approach. Moreover, the high affinity shown by homobivalent ligands suggests that bivalency is a promising approach in 5-HT3 Receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 Receptor function.

  • novel potent 5 ht3 Receptor ligands based on the pyrrolidone structure synthesis biological evaluation and computational rationalization of the ligand Receptor interaction modalities
    Bioorganic & Medicinal Chemistry, 2002
    Co-Authors: Andrea Cappelli, Maurizio Anzini, Salvatore Vomero, Michel Hamon, Laura Mennuni, Francesco Makovec, E. Doucet, Cristina M Menziani, Pier G De Benedetti, Gianluca Giorgi
    Abstract:

    Abstract Novel conformationally constrained derivatives of classical 5-HT3 Receptor antagonists were designed and synthesized with the aim of probing the central 5-HT3 Receptor recognition site in a systematic way. The newly-synthesized compounds were tested for their potential ability to inhibit [3H]granisetron specific binding to 5-HT3 Receptor in rat cortical membranes. These studies revealed subnanomolar affinity in some of the compounds under study. The most potent ligand in this series was found to be quinuclidine derivative (S)-7i, which showed an affinity comparable with that of the reference ligand granisetron. The potential 5-HT3 agonist/antagonist activity of some selected compounds was assessed in vitro on the 5-HT3 Receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Both of the tropane derivatives tested in this functional assay (7a and 9a) showed antagonist properties, while the quinuclidine derivatives studied [the enantiomers of compounds 7i, 8g, and 9g, and compound (R)-8h] showed a full range of intrinsic efficacies. Therefore, the functional behavior of these 5-HT3 Receptor ligands appears to be affected by the structural features of both the azabicyclo moiety and the heteroaromatic portion. In agreement with the data obtained on NG 108-15 cells, investigations on the 5-HT3 Receptor-dependent Bezold–Jarisch reflex in urethane-anaesthetized rats confirmed the 5-HT3 Receptor antagonist properties of compounds 7a and (S)-7i showing for these compounds ID50 values of 2.8 and 181 μg/kg, respectively. Finally, compounds 7a, (S)-7i and 9a (at the doses of 0.01, 1.0, and 0.01 mg/kg ip, respectively) prevented scopolamine-induced amnesia in the mouse passive avoidance test suggestive of a potential usefulness in cognitive disorders for these compounds. Qualitative and quantitative structure–affinity relationship studies were carried out by means of theoretical descriptors derived on a single structure and ad-hoc defined size and shape descriptors (indirect approach). The results showed to be useful in capturing information relevant to ligand–Receptor interaction. Additional information derived by the analysis of the energy minimized 3-D structures of the ligand–Receptor complexes (direct approach) suggested interesting mechanistic and methodological considerations on the binding mode multiplicity at the 5-HT3 Receptors and on the degree of tolerance allowed in the alignment of molecules for the indirect approach, respectively.

  • Novel potent and selective central 5-HT3 Receptor ligands provided with different intrinsic efficacy. 2. Molecular basis of the intrinsic efficacy of arylpiperazine derivatives at the central 5-HT3 Receptors
    Journal of medicinal chemistry, 1999
    Co-Authors: Andrea Cappelli, Maurizio Anzini, Salvatore Vomero, Michel Hamon, Laura Mennuni, Maria Cristina Menziani, Francesco Makovec, E. Doucet, Laura Canullo, Pier G De Benedetti
    Abstract:

    Novel 5-HT3 Receptor ligands were designed and synthesized with the aim of obtaining deeper insight into the molecular basis of the intrinsic efficacy of arylpiperazines interacting with the central 5-HT3 Receptor. The newly synthesized compounds and some previously published compounds belonging to the same class of heteroarylpiperazines were tested for their potential ability to displace [3H]granisetron from rat cortical membranes. These 5-HT3 Receptor binding studies revealed subnanomolar affinity in several of the compounds under study. The most active ligands were quipazine derivatives bearing a phenyl group in the 4-position and various oxygenated alkyl side chains in the 3-position of the quinoline nucleus. Qualitative and theoretical quantitative structure-affinity relationship studies were carried out, and the interaction model for the 5-HT3 ligands related to quipazine with their Receptor, proposed in part 1 of the present work, was updated to incorporate the latest data. The potential 5-HT3 agonist/antagonist activity of 12 selected compounds was assessed in vitro on the 5-HT3 Receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Their intrinsic efficacy ranged from the 5-HT3 full agonist properties of compounds 7a and 8h, i to those of partial agonists 10a,d and antagonists 8b,d,e, and 9c, d,h,i. The comparison between these functional data and those relative to the previously described compounds suggested that in this class of 5-HT3 ligands the intrinsic efficacy is modulated in a rather subtle manner by the steric features of the heteroaryl moiety.