Motilin is a 22-amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract of humans and other species. It affects gastric motility by stimulating interdigestive antrum and duodenal contractions. A heterotrimeric guanosine triphosphate-binding protein (G protein)-coupled receptor for motilin was isolated from human stomach, and its amino acid sequence was found to be 52 percent identical to the human receptor for growth hormone secretagogues. The macrolide antibiotic erythromycin also interacted with the cloned motilin receptor, providing a molecular basis for its effects on the human GI tract. The motilin receptor is expressed in enteric neurons of the human duodenum and colon. Development of motilin receptor agonists and antagonists may be useful in the treatment of multiple disorders of GI motility.
Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.
Finasteride is employed in treatment of benign
prostatic hyperplasia in man, where its target enzyme is
steroid 5α-reductase. It is a novel, potent mechanism-based
inhibitor of the human prostate (type 2) isozyme.
Although
it is accepted as an alternate substrate and is ultimately reduced to
dihydrofinasteride, this proceeds through an
enzyme-bound NADP−dihydrofinasteride adduct. Finasteride is
processed with a second-order rate constant,
k
i/K
i
= 1 × 106 M-1
s-1, that approaches
k
cat/K
m for reduction of
testosterone, 3 × 106 M-1
s-1, and essentially every
catalytic event is lethal (partition ratio ≤ 1.07). The
membrane-bound enzyme−inhibitor complex formed from
[3H]finasteride appears to release
[3H]dihydrofinasteride with a half-life of 1 month
at 37 °C (k = (2.57 ± 0.03) ×
10-7 s-1), as identified by mass
spectroscopy. The intermediate NADP−dihydrofinasteride adduct
can be recovered
intact by denaturation of the enzyme−inhibitor complex and has been
purified. Free in solution, it likewise decomposes
to dihydrofinasteride (half-life = 11 days). An extremely potent
bisubstrate analog inhibitor, this NADP−dihydrofinasteride adduct binds to the free enzyme with a second-order
rate constant equal to
k
cat/K
m for turnover
of
testosterone and has a dissociation constant K
i
≤ 1 × 10-13 M. Finasteride is also a
mechanism-based inhibitor of
the human skin (type 1) isozyme, but it is processed with a much
smaller second-order rate constant,
k
i/K
i = 3 ×
103
M-1 s-1, which
attenuates its activity against this isozyme in vivo. The
mechanism explains the exceptional potency
and specificity of finasteride in treatment of benign prostatic
hyperplasia, and the concept may have application to
other pyridine nucleotide-linked enzymes.
We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain.
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