Jeffrey S. Nissen

Comparison of the effects of serotonin selective, norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats

Previous studies showed that the dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor, duloxetine, increases bladder capacity and urethral sphincter electromyographic (EMG) activity in a cat model of acetic acid-induced bladder irritation. The present study aimed to determine the relative importance of 5-HT versus NE reuptake inhibition for mediating these effects by examining drugs that are selective for either the 5-HT or NE system or both. Similar to duloxetine, venlafaxine (0.1 to 10 mg/kg), also a dual serotonin and norepinephrine reuptake inhibitor, produced marked increases in bladder capacity and EMG activity that were reversed by methiothepin (0.3 mg/kg). S-norfluoxetine (0.01 to 10 mg/kg), a serotonin selective reuptake inhibitor, produced small but significant increases in bladder capacity and EMG activity at doses of 3 and 10 mg/kg. Thionisoxetine (0.01 to 3.0 mg/kg), a NE selective reuptake inhibitor, produced no effects on bladder capacity or sphincter EMG activity. Surprisingly, co-administration of thionisoxetine and s-norfluoxetine up to doses of 1 mg/kg of each compound produced no effect on lower urinary tract function. These doses were the maximum that could be administered in combination due to drug-induced emergence of skeletal muscle activity in chloralose-anesthetized animals. These results indicate that there are unexplained pharmacological differences between the effects of single compounds that exhibit dual NE and 5-HT reuptake inhibition and a combination of compounds that exhibit selective NE and 5-HT reuptake inhibition on lower urinary tract function.

N(1)-substituted ergolines and tryptamines show species differences for the agonist-labeled 5-HT2 receptor

Previous studies indicated that selected ergolines and tryptamines showed species differences for affinity to the antagonist-labeled 5-HT2 receptor. The present study examined these same compounds for affinity at the agonist-labeled 5-HT2 receptor in rat and squirrel monkey cortical homogenates using [125I]DOI ([125I]1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane). As seen with the antagonist-labeled 5-HT2 receptor, N(1) alkyl substitution of either the ergolines or tryptamines resulted in a slight increase or no effect on their affinity for the agonist-labeled rat 5-HT2 receptor. In contrast, these same N(1) substitutions resulted in significant decreases in affinity for the agonist-labeled monkey 5-HT2 receptor. It was also noted that N(1)-unsubstituted ergolines and tryptamines (such as ergonovine, LY86057, LY193525 and 5-methoxytryptamine) tended to have higher affinity for the monkey versus the rat agonist-labeled receptor. However, the N(1) alkyl-substituted ergolines and tryptamines (such as mesulergine, LY53857, amesergide, N(1)-isopropyltryptamine and N(1)-isopropyl-5-methoxytryptamine) showed significantly lower affinity for the monkey versus the rat 5-HT2 receptor. These data suggest that, at least in relation to the N(1) position, ergolines and tryptamines bind in a similar orientation. These results are also discussed in terms of what amino acid differences between species may account for this structure-activity relationship.

A series of C-Terminal amino alcohol dipeptide Aβ inhibitors

Potent, small molecule Aβ inhibitors have been prepared that incorporate an alanine core bracketed by an N-terminal arylacetyl group and various C-terminal amino alcohols. The compounds exhibit stereospecific inhibition as demonstrated in an in vitro assay.

Molecular orbital study of the structure and interactions of ylidene rhodanines

Semiempirical (with the AM1 Hamiltonian) and ab initio (mainly with the 6-31G* and LANL2DZ+ +(d,p) basis sets) molecular oribital calculations show the predominant tautomer of gas phase methylidene rhodanine is 2-thioxo-4-thiazolidinone in agreement with earlier work on other types of rhodanines. Inclusion of solvation effects in the AM1 calculations corroborates with this tautomer is also preferred in aqueous solution. Energy-optimized bond lengths and angles show good agreement with those for a crystalline benzylidene rhodanine. The geometry of a hydrogen bonded dimer matches closely the crystalline state arrangement. The two N-H ⋯ O hydrogen bonds that form in the dimer. provide a stabilization energy of about - 10 kcal/mol. The interactions of methylidene rhodanine with a calcium ion are modeled with basis sets as large as LANL2DZ+ +(d,p). The preferred binding site is near the carbonyl oxygen for the neutral rhodanine and near the nitrogen and thione sulfur in a bidentate arrangement for the rhodanine anion. Implications for the interaction of benzylidene rhodanines with various possible protein and metalloprotein receptors are discussed.