Prolonged D2 antidopaminergic activity of alkylating and nonalkylating derivatives of spiperone in rat brain
Baldessarini, R.J.; Kula, N.S.; Campbell, A.; Bakthavachalam, V.; Yuan, J.; Neumeyer, J.L.
Molecular Pharmacology 42(5): 856-863
1992
ISSN/ISBN: 0026-895X PMID: 1435753 Document Number: 400722
Alkyl and arylalkyl derivatives of the dopamine (DA) D-2 antagonist spiperone were prepared and characterized chemically and pharmacologically. They included the N-methyl, N-phenethyl (NPS), and N-p-aminophenethyl (NAPS) derivatives, as well as the alkylating isothiocyanato (NIPS), bromacetamido, and ethylfumaramido p-substituted N-phenethylspiperones. These compounds showed high lipophilicity (log P up to 6.0 with NIPS), as well as very high in vitro D-2 affinity (K-i = 35-280 pM) and D-2 versus D-1 selectivity (540-9000-fold) in radioreceptor assays with corpus striatum of rat brain. Of the alkylating series, NIPS showed the highest D-2 affinity (57 pM) and D-2 versus D-1 selectivity (2040-fold) and so was selected for further evaluation. NPS, NAPS, and NIPS showed little or no affinity for 34 non-DA binding sites defined by radioligand assays for monoamine, amino acid, and peptide neurotransmitters, ion channels, peptide growth factors, and transmission mediators but did show low alpha-2 and moderate alpha-1 and 5-hydroxytryptamine (5-HT-2) affinity with rat forebrain tissue in vitro; NIPS showed a marked gain in D-2 versus 5-HT-2 selectivity, compared with spiperone (1520- versus 26-fold). Systemic injections of NIPS induced marked decreases in rat striatal D-2 binding sites 24 hr later, with little effect on D-1, 5-HT-2, or alpha-1 sites; NIPS and NAPS lowered apparent B-max values at D-2 receptors with little change in ligand affinity, ex vivo as well as in vitro. NPS, NAPS, and NIPS all induced dose-dependent lowering of D-2 binding ex vivo (ID-50 = 1-9 mu-mol/kg, intraperitoneally) and blocked the behavioral effects of the DA agonist apomorphine (0.9 mu-mol/kg) potently (ID-50 = 0.3-0.5 mu-mol/kg) at 24 hr. Recovery from these anti-DA actions required about 1 week after equimolar (15 mu-mol/kg) and similarly effective doses of NPS and NAPS, as well as NIPS. Thus, highly selective and avidly bound lipophilic D-2 affinity ligands with similarly avid in vitro and prolonged in vivo anti-DA activities can be derived from N-phenethylspiperones with or without an alkylating moiety present. Such affinity ligands may represent useful additions to previously used, generally less selective, D-2 affinity ligands.