U-50,488H is a chemically novel analgesic that is a potent opioid-like agent on the mouse tail flick and electrically stimulated guinea pig ileum tests. U-50,488H is a very weak competitor for naloxone binding sites in brain and ileum. However, the drug has high affinity for kappa receptor binding sites revealed by competition for EKC sites in the presence of dihydromorphine. Morphine has both supraspinal and spinal sites of action since it was a potent analgesic after both intracranial and intraspinal injections. However, U-50,488H works predominantly at the spinal level. Dynorphin may be an endogenous ligand at this site. Studies on cat dorsal horn neurons suggest that U-50,488H analgesia may be due to an increase in threshold for neuron excitation.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMedDate not supplied

Pharmacology of pramipexole, a dopamine D3-preferring agonist useful in treating Parkinson's disease.

Pramipexole is a clinically effective nonergot dopamine agonist. Pramipexole's receptor interactions differ from ergot agonists in several ways. First, it has high selectivity for interacting with dopamine D2 subfamily receptors (D2, D3, and D4 receptor subtypes) and has little interaction with adrenergic or serotonergic receptors. Second, within the D2 subfamily, it has preferential affinity for the D3 receptor subtype, which, according to preclinical studies, could contribute additional efficacy for treatment of both motor and psychiatric syndromes in Parkinson's disease. Third, it has full intrinsic activity at dopamine D2 subfamily receptors. In addition to pramipexole's unusual receptor profile, whole-animal and cell culture studies suggest that pramipexole might provide neuroprotective effects through depression of dopamine metabolism, antioxidant effects, and stimulation of trophic activity. Pramipexole's demonstrated clinical efficacy for successful treatment in early disease for several years in the absence of L-dopa and as adjunctive therapy with L-dopa in late disease suggests a potential new paradigm for treatment of Parkinson's disease whereby new patients are initiated with pramipexole therapy and L-dopa is added only as necessary.

Aged↗