Publications by authors named "Brian S Fulton"
Acute and chronic effects of the M1/M4-preferring muscarinic agonist xanomeline on cocaine vs. food choice in rats.
Psychopharmacology (Berl)
February 2014
Article Synopsis
- - The study investigates the effects of xanomeline, a muscarinic agonist, on cocaine self-administration in rats, finding that chronic administration can shift behavior from cocaine use to food reinforcement without developing tolerance.
- - Xanomeline pretreatment demonstrated a significant impact on reducing cocaine's effectiveness, evidenced by a rightward shift in the dose-effect curve and an increase in food-reinforced behavior, but the effects were sometimes overwhelmed by high doses of cocaine.
- - Although results indicated a potential for xanomeline to promote abstinence from cocaine, the findings were mixed regarding its clinical applicability, suggesting the need for further research on other compounds that may have better selectivity and efficacy.
Article Synopsis
- The study investigates how muscarinic agonists targeting M(1) and M(4) receptors influence cocaine discrimination and self-administration in mice, highlighting previous findings that these effects don't occur in mice lacking both receptor types (double-knockout).
- Through experiments with various agonists, it was found that the effectiveness of drugs like xanomeline and VU0357017 in reducing the effects of cocaine depends on the presence of M(1) receptors, with xanomeline requiring both M(1) and M(4) for optimal effect.
- Results suggest that drugs selectively targeting M(1) and mixed M(1)/M(4) agonists could be potential candidates
A series of bivalent hydroxy ether butorphan ligands were prepared and their binding affinities at the opioid receptors determined. Addition of a hydroxy group to a hydrocarbon chain can potentiate binding affinity up to 27- and 86-fold at the mu and kappa opioid receptors, respectively. Two bivalent ligands with sub-nanomolar binding affinity at the mu and kappa opioid receptors were discovered.
View Article and Find Full Text PDFModulation of prepulse inhibition through both M(1) and M (4) muscarinic receptors in mice.
Psychopharmacology (Berl)
February 2010
Article Synopsis
- The study explores the impact of muscarinic cholinergic M(1) and M(4) receptors on behaviors related to schizophrenia using genetically modified mice (knockout mice) lacking these receptors.
- Results indicated that deleting both M(1) and M(4) receptors reduces prepulse inhibition (PPI), a measure of sensorimotor gating, especially in female mice, while blocking either receptor alone showed no significant change.
- Findings suggest that M(1) and M(4) receptors play a combined role in PPI regulation, with the antipsychotic effects of some drugs, like xanomeline, likely linked to M(4) receptor activity, but not clozapine's effectiveness being
Article Synopsis
- Muscarinic cholinergic receptors influence how the brain responds to cocaine, which is important for understanding its addictive properties.
- Researchers tested different muscarinic receptor antagonists and agonists on mice trained to differentiate between cocaine and saline, finding that antagonists enhanced cocaine's effects while agonists reduced them.
- Results indicate that activating the M(1) receptor can help reduce cocaine's abuse-related effects, while other non-M(1)/M(4) receptor activities may lead to negative side effects.
Bivalent morphinan compounds containing ester linkers were synthesized and their binding affinities at the mu, delta, and kappa opioid receptors determined. Addition of methyl groups adjacent to the hydrolytically labile ester linkage increased stability while only partially affecting binding affinity. The resulting bivalent ligands with optimized spacer length and structure show potent binding profiles with the most potent compound (4b), having K(i) values of 0.
View Article and Find Full Text PDFWe synthesized several hydrophobic esters and ethers of butorphanol and assessed their affinities at opioid receptors in CHO cell membranes. Tested compounds displayed moderate to high affinities to the mu and kappa receptors. The findings accord with previous evidence of a lipophilic binding pocket in the opioid receptors that can be accessed to afford good binding affinity without the need for a phenolic hydrogen-bond donor group.
View Article and Find Full Text PDFOnce opioid receptor dimers were postulated, a goal has been to synthesize and screen novel opioids, with the hope of furthering our knowledge of the structure-activity relationship of opioid ligands with the opioid receptors. The aim of the current study was to address whether two isomeric bivalent ligands would have pharmacological differences after central administration, in vivo. The two compounds, (-) bis(N-cyclobutylmethyl-morphinan-3-yl) sebacoylate dihydrochloride (MCL-144) and 1-((+)N-cyclobutylmethylmorphinan-3-yl)-10-((-) N-cyclobutylmethylmorphinan-3-yl)sebacolyate (MCL-193) are each linked by a 10-carbon chain ester.
View Article and Find Full Text PDF