The total synthesis of the Hakomori MBr1 antigen, heavily
expressed on human breast tumors, is related.
The construction involved the assembly of four glycals:
(17 (twice), 18, 20, and
26) and an l-fucose derivative,
34.
The sensitivity of the stereochemistry of sulfonamido
galactosylation by a terminal galactose ring as a function
of
the state of protection status of its C4 alcohol was
exploited in a key step. (See the formation of compound
51.)
The synthesis served to confirm the Hakomori assignment of
structure, and paves the way for immunoconjugation.
(See compound 64.)
The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity.
The photophysics and photochemistry of cis-locked retinal analogues have been investigated by steady-state and by picosecond and nanosecond time-resolved techniques. We have found that retinal analogues locked into the 11,12-cis configuration via bridged 8-and 9-membered rings, Ret-8 and Ret-9, respectively, are restricted in twisting about the 11,12 double bond in the first triplet state, T 1 . The twisting is restricted to different extents depending on the size of the ring. In the case of Ret-8, no geometric isomerization occurs following photoexcitation. This contrasts cis-cyclooctene derivatives which can be photoisomerized to thermodynamically less favored trans-cyclooctene. The result is rationalized by noting that in Ret-8 the ring incorporates four consecutive sp 2 carbons whereas the latter has only two. For Ret-9 which has one extra carbon in the ring, however, "cis-trans isomerization" becomes possible resulting in shorter-lived excited states and a detectable transient on the nanosecond time scale which is assigned to a short-lived (τ ≈ 110 ns) transoid ground state species.
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