The synthesis and in vitro and in vivo evaluation of a series of 3-(benzyloxy)-1-azabicyclo-[2.2.... more The synthesis and in vitro and in vivo evaluation of a series of 3-(benzyloxy)-1-azabicyclo-[2.2.2]octane NK1 antagonists are described. While a number of 3,5-disubstituted benzyl ethers afford high affinity, the 3,5-bis(trifluoromethyl)benzyl was found to combine high in vitro affinity with good oral activity. Detailed structure-activity relationship studies in conjunction with data from molecular modeling and mutagenesis work have allowed the construction of a model of the pharmacophore. Specific interactions that have been identified include an interaction between His-197 and one of the rings of the benzhydryl, a lipophilic pocket containing His-265 that the benzyl ether occupies, and a possible hydrogen bond between Gln-165 and the oxygen of the benzyl ether.
The Journal of Pharmacology and Experimental Therapeutics, May 1, 1987
High doses of methamphetamine (METH) induced 200 to 300% increases in the neurotensin-like immuno... more High doses of methamphetamine (METH) induced 200 to 300% increases in the neurotensin-like immunoreactivity (NTLI) concentrations of the substantia nigra and striatum in rats after a single or multiple drug doses; smaller but significant increases of 30 to 50% were observed in the hypothalamus and hippocampus after multiple, but not single, METH administrations whereas no measurable changes were detected in the NTLI levels of the periaqueductal gray area or the amygdala. These METH-induced increases in NTLI concentrations were attenuated by coadministration of haloperidol in the substantia nigra, hypothalamus and hippocampus, indicating a possible involvement of dopamine receptors in these tissues. In the striatum haloperidol alone produced significant increases in NTLI levels; these increases were additive with those induced by METH treatment demonstrating that the neurotensin pathways associated with the striatum are regulated differently from that of the other brain areas examined. The implications of these findings to the relationship between dopamine and neurotensin transmitter systems are discussed.
In the rat, administration of the psychoactive analog of amphetamine 3,4-methylenedioxymethamphet... more In the rat, administration of the psychoactive analog of amphetamine 3,4-methylenedioxymethamphetamine (MDMA), causes selective, pronounced decreases in markers of central serotonergic function. The time course of these neurochemical changes was examined in several serotonergic nerve terminal regions of the brain. Fifteen min after subcutaneous injection of MDMA (10 mg/kg), the enzymatic activity of tryptophan hydroxylase (the rate-limiting enzyme for the biosynthesis of serotonin) was significantly decreased in the frontal cortex; by 1 hr after the injection, the activity of tryptophan hydroxylase had significantly declined in the neostriatum, hippocampus and hypothalamus as well. Although extensive recovery had occurred by 2 weeks, the activity of the enzyme remained significantly depressed in most regions. Decline of the regional content of 5-hydroxytryptamine (5-HT) closely paralleled, but was usually preceded by, that of the enzyme. Concentrations of the primary metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), were less responsive: in most regions levels of 5-HIAA had significantly decreased by 3 hr, but not by 1 hr, following treatment. Markers of dopamine function were altered transiently but had returned to control values by 24 hr. Administration of multiple doses of MDMA (5 doses over a 24-hr period) resulted in significant decreases in serotonergic parameters for up to 110 days after treatment. The rate and extent of recovery varied according to both the dose administered and the region examined. The persistence of these serotonergic deficits suggests that MDMA induced the destruction of serotonin-containing axon terminals.
Recent studies have described novel azabicycle-based muscarinic agonists which readily penetrate ... more Recent studies have described novel azabicycle-based muscarinic agonists which readily penetrate into the central nervous system and are capable of displaying high efficacy at cortical sites. The current paper describes the synthesis and biochemical assessment of semirigid muscarinic ligands which were used to map the requirements of the cortical muscarinic receptor and to study the degree of conformational flexibility required to cause receptor activation. Analogues 6 and 9 provide high-efficacy muscarinic agonists at cortical sites; however, C-alkylation on the tetrahydropyridine ring resulted in more rigid analogues and showed lower predicted efficacy. Molecular mechanics calculations indicated a preference for the E rotameric form. This conformation was also observed in the X-ray crystal structure of ethenyloxadiazole 12. The new compounds were tested in a biochemical assay designed to measure receptor affinity and to predict cortical efficacy.
A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinu... more A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and 1-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hydrolysis and decarboxylation. The receptor-binding affinity and efficacy of these compounds as muscarinic ligands was assessed by radioligand binding assays using [3H]-N-methylscopolamine and [3H]oxotremorine-M. Optimal agonist affinity was observed for 3'-methyl compounds. Smaller substituents (H) retained efficacy with reduced affinity while larger groups led to substantially lower efficacy. The observed binding affinity was influenced both by the conformational energy of rotation around the C3-C5' bond and the steric requirement of the mono- or bicyclic amine.
... Receptor Antagonists. Kevin J. Merchant*, Richard T. Lewis and Angus M. MacLeod. Merd ... 251... more ... Receptor Antagonists. Kevin J. Merchant*, Richard T. Lewis and Angus M. MacLeod. Merd ... 251,435-437. 6. MwLcod.AM; Merchant, KJ; Cascieri.MA.; Sadowdd, S.; Ber, E.; Swain, CJ; Baker, RJ Med.Chem. 1993,36,2044-2045. 7 ...
The synthesis and in vitro and in vivo evaluation of a series of 3-(benzyloxy)-1-azabicyclo-[2.2.... more The synthesis and in vitro and in vivo evaluation of a series of 3-(benzyloxy)-1-azabicyclo-[2.2.2]octane NK1 antagonists are described. While a number of 3,5-disubstituted benzyl ethers afford high affinity, the 3,5-bis(trifluoromethyl)benzyl was found to combine high in vitro affinity with good oral activity. Detailed structure-activity relationship studies in conjunction with data from molecular modeling and mutagenesis work have allowed the construction of a model of the pharmacophore. Specific interactions that have been identified include an interaction between His-197 and one of the rings of the benzhydryl, a lipophilic pocket containing His-265 that the benzyl ether occupies, and a possible hydrogen bond between Gln-165 and the oxygen of the benzyl ether.
The Journal of Pharmacology and Experimental Therapeutics, May 1, 1987
High doses of methamphetamine (METH) induced 200 to 300% increases in the neurotensin-like immuno... more High doses of methamphetamine (METH) induced 200 to 300% increases in the neurotensin-like immunoreactivity (NTLI) concentrations of the substantia nigra and striatum in rats after a single or multiple drug doses; smaller but significant increases of 30 to 50% were observed in the hypothalamus and hippocampus after multiple, but not single, METH administrations whereas no measurable changes were detected in the NTLI levels of the periaqueductal gray area or the amygdala. These METH-induced increases in NTLI concentrations were attenuated by coadministration of haloperidol in the substantia nigra, hypothalamus and hippocampus, indicating a possible involvement of dopamine receptors in these tissues. In the striatum haloperidol alone produced significant increases in NTLI levels; these increases were additive with those induced by METH treatment demonstrating that the neurotensin pathways associated with the striatum are regulated differently from that of the other brain areas examined. The implications of these findings to the relationship between dopamine and neurotensin transmitter systems are discussed.
In the rat, administration of the psychoactive analog of amphetamine 3,4-methylenedioxymethamphet... more In the rat, administration of the psychoactive analog of amphetamine 3,4-methylenedioxymethamphetamine (MDMA), causes selective, pronounced decreases in markers of central serotonergic function. The time course of these neurochemical changes was examined in several serotonergic nerve terminal regions of the brain. Fifteen min after subcutaneous injection of MDMA (10 mg/kg), the enzymatic activity of tryptophan hydroxylase (the rate-limiting enzyme for the biosynthesis of serotonin) was significantly decreased in the frontal cortex; by 1 hr after the injection, the activity of tryptophan hydroxylase had significantly declined in the neostriatum, hippocampus and hypothalamus as well. Although extensive recovery had occurred by 2 weeks, the activity of the enzyme remained significantly depressed in most regions. Decline of the regional content of 5-hydroxytryptamine (5-HT) closely paralleled, but was usually preceded by, that of the enzyme. Concentrations of the primary metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), were less responsive: in most regions levels of 5-HIAA had significantly decreased by 3 hr, but not by 1 hr, following treatment. Markers of dopamine function were altered transiently but had returned to control values by 24 hr. Administration of multiple doses of MDMA (5 doses over a 24-hr period) resulted in significant decreases in serotonergic parameters for up to 110 days after treatment. The rate and extent of recovery varied according to both the dose administered and the region examined. The persistence of these serotonergic deficits suggests that MDMA induced the destruction of serotonin-containing axon terminals.
Recent studies have described novel azabicycle-based muscarinic agonists which readily penetrate ... more Recent studies have described novel azabicycle-based muscarinic agonists which readily penetrate into the central nervous system and are capable of displaying high efficacy at cortical sites. The current paper describes the synthesis and biochemical assessment of semirigid muscarinic ligands which were used to map the requirements of the cortical muscarinic receptor and to study the degree of conformational flexibility required to cause receptor activation. Analogues 6 and 9 provide high-efficacy muscarinic agonists at cortical sites; however, C-alkylation on the tetrahydropyridine ring resulted in more rigid analogues and showed lower predicted efficacy. Molecular mechanics calculations indicated a preference for the E rotameric form. This conformation was also observed in the X-ray crystal structure of ethenyloxadiazole 12. The new compounds were tested in a biochemical assay designed to measure receptor affinity and to predict cortical efficacy.
A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinu... more A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and 1-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hydrolysis and decarboxylation. The receptor-binding affinity and efficacy of these compounds as muscarinic ligands was assessed by radioligand binding assays using [3H]-N-methylscopolamine and [3H]oxotremorine-M. Optimal agonist affinity was observed for 3'-methyl compounds. Smaller substituents (H) retained efficacy with reduced affinity while larger groups led to substantially lower efficacy. The observed binding affinity was influenced both by the conformational energy of rotation around the C3-C5' bond and the steric requirement of the mono- or bicyclic amine.
... Receptor Antagonists. Kevin J. Merchant*, Richard T. Lewis and Angus M. MacLeod. Merd ... 251... more ... Receptor Antagonists. Kevin J. Merchant*, Richard T. Lewis and Angus M. MacLeod. Merd ... 251,435-437. 6. MwLcod.AM; Merchant, KJ; Cascieri.MA.; Sadowdd, S.; Ber, E.; Swain, CJ; Baker, RJ Med.Chem. 1993,36,2044-2045. 7 ...
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